We reviewed hundreds of papers published between April 1, 2009, and March 31, 2010, in preparation for this review. This year showed a “bumper crop” of excellent papers. Our intent was to include those papers that either yield new insights into disease mechanism or provide important therapeutic advances. We apologize for the required omission of many excellent studies.

Warfarin remains the most efficacious therapy available to prevent stroke in the setting of AF (1- 3). However, several substantial limitations of the drug have motivated research to develop superior alternatives. Perhaps most important, warfarin is associated with an increased risk of hemorrhagic stroke. In addition, the food and drug interactions and need for ongoing monitoring make the drug particularly difficult for patients to take. This year, several studies examining new therapies for stroke prevention in the setting of AF were published.

The first study is the first published major trial of a direct thrombin inhibitor since the SPORTIF (Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation) studies examining ximelagatran. Although ximelagatran appeared to be similar to warfarin in efficacy and bleeding risk, it resulted in hepatotoxicity (4). Connolly et al. (5) published the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study, a randomized trial that compared the blinded administration of 2 fixed doses of a new direct thrombin inhibitor, dabigatran, with open-labeled use of warfarin in patients with AF and at least 1 additional risk factor for stroke. A total of 18,113 AF patients were enrolled, with median follow-up of 2.0 years. The primary outcome of stroke or systemic embolism occurred in 182 patients receiving 110 mg twice daily of dabigatran (1.53% per year), 134 patients receiving 150 mg twice daily of dabigatran (1.11% per year), and 199 patients receiving warfarin (1.69% per year). Both doses of dabigatran were noninferior to warfarin (p < 0.001). The higher dose of dabigatran was also superior to warfarin (relative risk for the primary end point: 0.66, 95% confidence interval [CI]: 0.53 to 0.82, p < 0.001). Rates of hemorrhagic stroke were significantly smaller in those who received either dose of dabigatran (relative risk: 0.31, 95% CI: 0.17 to 0.56, p < 0.001 for the 110-mg dose; relative risk: 0.26, 95% CI: 0.14 to 0.49, p < 0.001 for the 150-mg dose) compared with those who received warfarin. Major bleeding was similar between the 150-mg dose of dabigatran and warfarin, but significantly less common in those on the 110-mg dose of dabigatran compared with warfarin (relative risk: 0.80, 95% CI: 0.69 to 0.93, p = 0.003). There was a significantly higher rate of major gastrointestinal bleeding with the higher dose of dabigatran compared with warfarin. The only adverse effect that was significantly more common with dabigatran compared with warfarin was dyspepsia. There were no significant differences in elevations of aspartate aminotransferase or alanine aminotransferase.

The RE-LY study therefore suggests that dabigatran may be an acceptable alternative to warfarin in AF patients with additional risk factors for stroke. The higher dose may have more efficacy, with a risk of hemorrhagic stroke and major bleeding comparable to that of warfarin and risk of gastrointestinal bleeding higher than that of warfarin. The lower dose of the drug appears to have comparable efficacy to warfarin, with evidence that there may be a lower bleeding risk. Therefore, future research, clinical experience, and expert consensus may teach us how to best risk stratify to determine optimal dosing for individual patients. Importantly, 80% of the active drug is excreted by the kidneys, and a creatinine clearance <30 ml was an exclusion criterion for the trial. Therefore, patients with significant renal impairment may not be candidates for this new therapy. In addition, to enhance absorption of dabigatran, a low pH is required. Therefore, the dabigatran capsules contain dabigatran-coated pellets with a tartaric acid core. This may explain the dyspepsia and higher rates of gastrointestinal bleeding with the higher dose. It also suggests that H2-blockers and proton pump inhibitors might affect the absorption and potentially reduce the efficacy of the drug.

The second trial studying a novel approach to stroke prevention in AF was the PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) trial investigating the WATCHMAN device (Atritech, Plymouth, Minnesota) (6). This is a self-expanding nickel titanium (nitinol) frame structure with fixation barbs and a permeable polyester fabric cover implanted via a transseptal approach to seal the left atrial appendage (7). Based on the findings that the left atrial appendage is the source of thrombi in more than 90% of patients with AF and building on pilot studies that showed acceptable risk-to-benefit ratios for this approach (8- 10), PROTECT AF enrolled 707 AF patients with an additional risk factor for stroke randomly assigned in a 2:1 ratio to percutaneous closure of the left atrial appendage or warfarin therapy. The device was successfully implanted in 88% of those assigned to the intervention. At the pre-specified 45-day follow-up, 86% of the device patients had a transesophageal echocardiogram that met the pre-defined criteria necessary to discontinue warfarin. After stopping warfarin, participants with the device were prescribed clopidogrel 75 mg daily and aspirin 81 mg daily. The clopidogrel was stopped after the 6-month follow-up visit. After a mean follow-up of 18 ± 10 months, the primary efficacy rate of stroke (including ischemic or hemorrhagic), cardiovascular or unexplained death, or systemic embolism was 3.0 per 100 patient-years (95% CI: 1.9 to 4.5) in the intervention group and 4.9 per 100 patient-years (95% CI: 2.8 to 7.1) in the control group. The probability of noninferiority to warfarin was >99.9% based on a 2-fold noninferiority margin. When the analysis was restricted to only those in the intervention group who had successful device implantation allowing for warfarin discontinuation, the device was found to be superior for this primary efficacy end point (rate ratio 0.40, 95% CI: 0.19 to 0.91). Ischemic strokes were more common in the intervention group, and hemorrhagic strokes were more common in the warfarin group. Complications of the device implant procedure included serious pericardial effusion in 22 (4.8%), procedure-related ischemic stroke attributed to air embolism in 5 (1.1%; these events were counted toward the total ischemic strokes in the intervention arm), and device embolization in 3 (0.6%). There were no deaths deemed related to the closure device.

PROTECT AF provides good evidence that a percutaneously placed left atrial appendage occlusion device might be a reasonable alternative to warfarin in patients with AF and additional stroke risk factors. The fact that those with successful closure fared better than those assigned to warfarin is proof of principle that the left atrial appendage is indeed likely the culprit in the majority of strokes due to AF. In interpreting the results of this important study, there are several considerations that should be kept in mind. Several important limitations of the study are described in an accompanying editorial (11), including the evident substantial learning curve associated with device implantation, the fact that approximately 10% of device patients who had discontinued warfarin restarted it for clinical reasons, the finding of thrombus formation on the device in 15 patients despite the prescribed warfarin and antiplatelet therapy, and the wide CIs in the primary efficacy estimate that resulted from relatively small numbers. In addition, although the groups were generally well balanced, patients in the control (warfarin) group more often had diabetes and permanent AF, but because no p values or CIs were provided for these estimates, it is not clear whether these differences were statistically significant. In addition, the device could not be successfully implanted in everyone, and even in those in whom it was implanted, warfarin could not be stopped on the basis of the pre-defined transesophageal echocardiogram criteria in everyone. Finally, because all device patients received warfarin until the device was well seated and the appendage sealed, this study does not address whether those with strict contraindications to warfarin should be considered for left atrial appendage closure.

The ACTIVE A (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) study addressed an approach that is immediately available in clinical practice for those AF patients with additional stroke risk factors that cannot take warfarin (12). Of note, the ACTIVE W trial previously showed that combination aspirin and clopidogrel was inferior to warfarin in stroke prevention in these patients (13). ACTIVE A enrolled 7,554 AF patients with at least 1 additional risk factor for stroke who were felt to be unsuitable for warfarin therapy. They were randomized to clopidogrel at 75 mg/day versus placebo in a double-blind fashion. All patients also received aspirin at a recommended dose of 75 to 100 mg/day. The primary outcome of any major vascular event (stroke, non-central nervous system embolism, myocardial infarction, or death from vascular causes) was 6.8% per year in the clopidogrel group versus 7.6% per year in the placebo group (relative risk: 0.89, 95% CI: 0.81 to 0.98, p = 0.01). This benefit was primarily due to a decrease in stroke. Patients in the clopidogrel group experienced major bleeding significantly more frequently than those in the placebo group (relative risk: 1.57, 95% CI: 1.29 to 1.92, p < 0.001). Although both severe major bleeding and intracranial bleeding were more common with clopidogrel, there were no detectable differences in hemorrhagic stroke or fatal bleeding. In sum, clopidogrel plus aspirin appears to be superior to aspirin alone in preventing stroke in the setting of AF, but at a cost of more bleeding. The benefit is somewhat incremental, but may be worthwhile in a patient deemed to be unsuitable for warfarin if the appropriate counseling regarding risks and benefits is performed.

The last alternative approach to stroke prevention in AF comes from a secondary analysis of the ATHENA (A placebo-controlled, double-blind, parallel-arm Trial to assess the efficacy of dronedarone 400 mg BID for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter) trial (14). Although it seems intuitive that maintenance of normal sinus rhythm in AF would lead to a reduction in strokes, well-conducted prospective studies comparing rhythm control with rate control failed to demonstrate such a difference (15- 16). Importantly, in these studies, vitamin K antagonists could be discontinued if there was evidence of sinus rhythm at follow-up in the rhythm control group. The majority of strokes occurred in those who either were not undergoing vitamin K antagonist therapy or in whom the international normalized ratio was subtherapeutic. Because AF can often be asymptomatic (17), the supposition has been that these patients thought to be in sinus rhythm were in fact having episodes of undetected AF. The main results of ATHENA were previously published (18). This analysis examined whether the 2,301 AF patients randomized to dronedarone experienced fewer strokes than the 2,327 AF patients randomized to placebo. All patients had at least 1 additional risk factor for stroke, and both groups had a mean CHADS₂ score of ∼2.0. Particularly important in interpreting this study is the fact that stroke outcomes were not pre-specified or centrally adjudicated. Instead, information regarding stroke was gathered from hospitalization reports and death reports. Strokes that did not lead to hospitalizations or death were reported as adverse events. Approximately 60% of all participants were receiving vitamin K antagonist therapy at baseline, and this was well balanced between the groups.

In ATHENA, there were 70 strokes with placebo (1.8% per year) compared with 46 strokes with dronedarone (1.2% per year), yielding a hazard ratio (HR) of 0.66 (95% CI: 0.46 to 0.96, p = 0.027). The Kaplan-Meier curves were noted to separate early and remain that way throughout the study. The investigators did not report whether this reduction in stroke was mediated by a reduction in AF. Of note, those receiving dronedarone exhibited a trend toward lower systolic blood pressure and a significant reduction in diastolic blood pressure compared with placebo, suggesting that the antihypertensive effect may have contributed to the lower rate of stroke. Finally, unlike previous studies examining antiarrhythmic agents and stroke prevention, the standard of practice had changed by the time this trial was conducted such that presence of sinus rhythm did not necessarily result in discontinuation of vitamin K antagonist therapy. Therefore, it remains unknown whether a similar effect might have been observed with other antiarrhythmic drugs if continuation of vitamin K antagonists had been uniform between rhythm and rate control groups.

Moving from stroke prevention in AF to treatment of symptoms due to AF, Wilber et al. (19) reported the ThermoCool AF trial, a prospective, multicenter, randomized (2:1) trial comparing open irrigated catheter ablation (n = 106) with antiarrhythmic drug therapy (n = 61). Enrollment required at least 3 symptomatic AF episodes in the last 6 months and failure to respond to at least 1 antiarrhythmic drug. In addition to follow-up at intermittent visits for symptoms of AF, all participants were required to transmit symptomatic episodes using trans-telephonic monitoring. For the ablation procedure, pulmonary vein isolation confirmed by entrance block was required, and additional lesion sets were allowed based on the treating physician's discretion. For those assigned to the drug arm, the choice of drug was at the discretion of the investigator. The majority in the drug arm received either flecainide or propafenone. A 3-month blanking period was in place after catheter ablation in the ablation arm, and a 14-day blanking period was in place during titration of medicines in the drug arm, during which efficacy was not assessed. Although repeat ablation procedures were allowed, the primary results reflected outcomes after a mean 1.1 procedures per patient. The primary end point of freedom from protocol-defined treatment failure, which included documented symptomatic paroxysmal AF during the 9-month effectiveness evaluation period, was 66% in the catheter ablation group and 16% in the antiarrhythmic drug group (HR: 0.30, 95% CI: 0.19 to 0.47, p < 0.001). There was also evidence based on serial SF-36 questionnaires that quality of life improved significantly in the ablation group compared with the antiarrhythmic drug group. Thirty-day major treatment-related adverse events occurred in 5 patients (5%) in the ablation group (1 pericardial effusion, 1 pulmonary edema, 1 pneumonia, 1 vascular complication, and 1 heart failure [HF]) and in 5 patients (9%) in the drug group (2 life-threatening arrhythmias and 3 with drug intolerance requiring discontinuation).

Although the ThermoCool AF trial appears to demonstrate superior efficacy in preventing symptomatic recurrent AF in those who received catheter ablation compared with those who received antiarrhythmic drug therapy, there are a few caveats to bear in mind. First, although this is the most rigorous, multicenter catheter ablation trial done to date, the centers involved were generally quite experienced in the procedure. The findings may therefore not apply to all centers. Because all patients had failed at least 1 antiarrhythmic drug and because the study was clearly not blinded, these presumably motivated patients might have subjectively favored their symptomatic response to an involved, invasive procedure. However, the investigators were careful to include trans-telephonic monitoring as well as Holter studies, with good evidence that AF was in fact substantially less common after ablation. In addition, those who failed drug therapy may represent patients who are destined to do poorly on drug treatment. The ongoing CABANA (Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) compares ablation with drugs as primary therapy. Although the 3-month blanking period after ablation is reasonable, this did result in less follow-up time for those undergoing ablation. In addition, some evidence suggests that, over time, late AF recurrence may return. Therefore, this 9-month efficacy end point (and mean follow-up of 12.5 months) may not be sufficient to teach us about long-term results.

Finally, a new risk factor for AF has recently emerged. Using data from the Framingham Heart Study, investigators examined the PR interval in 7,575 individuals as a predictor of incident AF, pacemaker implantation, and mortality (20). Dichotomizing the PR interval into >200 ms or not (i.e., first-degree heart block or not), they found that first-degree heart block was associated with an unadjusted HR of 4.26 (95% CI: 2.85 to 6.38) for AF (absolute increase, 1.04% per person-year), 10.26 (95% CI: 6.66 to 15.82) for pacemaker implantation, and 2.72 (95% CI: 2.11 to 3.51) for all-cause mortality. After multivariable adjustment, an increasing PR interval was associated with an increased risk for each of these outcomes. Similar results were observed after excluding individuals taking nodal-blocking medications. There was previously a perception that a first-degree AV block was benign (21- 23), and this well-conducted study suggests this may not in fact be the case. Although there is currently no clear therapeutic option that would necessarily change the management for an individual found to have first-degree AV block, and although the number needed to harm for AF was 96 (i.e., most individuals with first-degree AV block will not develop AF), these findings may help identify patients at risk for AF in combination with other risk factors (24) and may help reveal mechanisms responsible for the disease. In fact, there are several potential mechanisms that might be responsible: a longer PR interval may be due to atrial fibrosis and decreased atrial conduction time. Or, it might reflect general fibrosis, affecting both the conduction system and the atria. It may also reflect greater vagal tone, which might also be responsible for AF. Finally, the long PR might itself have hemodynamic consequences that lead to AF.

The meaning of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) in the setting of a high-risk ST-segment elevation myocardial infarction (STEMI) was studied as a secondary analysis of the APEX AMI (Assessment of Pexelizumab in Acute Myocardial Infarction) trial (25). Of 5,745 acute STEMI patients felt to be high risk (mainly excluding isolated inferior wall STEMI), sustained VT/VF occurred in 329 (5.7%). Twenty-five patients had the arrhythmia before cardiac catheterization, 180 had it during the cardiac catheterization procedure, and 117 had the event after the procedure. Ninety percent occurred within 48 h. Those receiving beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or statins had VT/VF less often, and those on class I and III antiarrhythmic drugs, receiving an intra-aortic balloon pump, undergoing repeat cardiac catheterization, undergoing dialysis, or requiring a blood transfusion more often had VT/VF. Important predictors of either early (before completion of the cardiac catheterization) or late (after the procedure) VT/VF were higher baseline heart rate, lower systolic blood pressure, higher baseline ST-segment deviation, and lower pre-procedural Thrombolysis In Myocardial Infarction (TIMI) flow grade. Higher Killip class, inferior myocardial infarction, lower creatinine clearance, shorter time from symptom onset to randomization, and higher weight were associated with early VT/VF. Post-procedural TIMI flow grade <3, lack of beta-blockers on admission, and ST-segment resolution <70% were associated with late VT/VF. Mortality in those with any VT/VF was significantly higher than those without it (23.2% vs. 3.6%, HR: 7.33, 95% CI: 5.61 to 9.59). The excess mortality was mainly confined to the first 30 days and was more common in those with late VT/VF. After adjustment for potential confounders, VT/VF remained associated with a significant increase in mortality. Of note, 70 (91%) of the deaths occurring in the VT/VF patients were cardiovascular, and of these, 30 (43%) were due to sudden cardiac death. Of interest, a similar proportion of those with no VT/VF had sudden death (36%, p = 0.67). Therefore, the mechanism of death may be related to the generally sicker hearts and/or the conditions associated with more VT/VF. It remains unknown whether the ventricular arrhythmia is causally related to worse outcomes or whether it simply reflects worse heart disease.

Recently, early repolarization or J-point elevation in the inferior and lateral leads has been shown to be more common in patients with idiopathic VF compared with controls (26- 27). Although the association appears to be quite strong, the risk of an adverse event when confronted with an asymptomatic patient with early repolarization remained unknown. Investigators in Finland examined the baseline electrocardiograms (ECGs) in 10,864 subjects in the Social Insurance Institution's Coronary Heart Disease Study that were obtained between 1966 and 1972 (28). Early-repolarization patterns were sought in the inferior and lateral leads and stratified according to the degree of J-point elevation (≥0.1 or ≥0.2 mV) that was either notched or slurred in 2 consecutive leads. The cause of death was determined by examining death certificates. All deaths from a cardiac cause were then reviewed, including review of hospital records, to determine whether the death was likely associated with an arrhythmia or not. J-point elevation of at least 0.1 mV was present in 630 (5.8%) of participants at baseline. Those with inferior lead J-point elevation were more often male, smokers, had a lower resting heart rate, a lower body mass index, lower blood pressure, a shorter QTc interval, a longer QRS duration, and were more likely to have ECG evidence of coronary artery disease. Those with lateral J-point elevation were more likely to have left ventricular hypertrophy. During follow-up of 30 ± 11 years, 613 (56.5%) patients died. Of these deaths, 1,969 (32%) were due to cardiac causes, and of those, 795 (40%) were sudden. Before and after multivariable adjustment, subjects with J-point elevation of at least 0.1 mV in the inferior leads (n = 384) had a higher risk of cardiac death (adjusted relative risk: 1.28, 95% CI: 1.04 to 1.59, p = 0.03) and arrhythmic death (adjusted relative risk: 1.43, 95% CI: 1.06 to 1.94, p = 0.03). However, these patients did not have a significantly higher rate of all-cause mortality. Before and after multivariable adjustment, subjects with J-point elevation of >0.2 mV (n = 36) had an increased risk of cardiac death (adjusted relative risk: 2.98, 95% CI: 1.85 to 4.92, p = 0.03), arrhythmic death (adjusted relative risk: 3.94, 95% CI: 1.96 to 7.90, p = 0.03), and death from any cause (adjusted relative risk: 1.54, 95% CI: 1.06 to 2.24, p = 0.03). Although J-point elevation in the lateral leads was associated with arrhythmic death, it predicted cardiac and all-cause death with borderline significance. Early repolarization appears to be associated with worse cardiovascular outcomes, but the exact mechanism remains to be elucidated. The mechanism may also differ between patients. Although the event rates were relatively high, particularly in those with J-point elevation >2.0 mV, the follow-up was quite long. Additional research is needed to narrow down the particular patients at highest risk and to inform us about screening strategies and ultimately preventive therapies. It does appear that inferior lead J-point elevation and particularly prominent J-point elevation may be important risk factors.

Although an implantable cardioverter-defibrillator (ICD) is an effective tool for secondary prevention in individuals who have suffered a cardiac arrest without a reversible cause (29- 30), determining the etiology of the event remains important. Although coronary artery disease and systolic dysfunction represent the most common precipitants, cardiac arrest survivors without evident cardiac disease remain a challenge to diagnose. Determining the cause can help guide adjuvant therapy (potentially helping to reduce palpitations, syncope, and ICD shocks), can help inform appropriate patient counseling regarding activity and particular drugs to avoid, and can help determine whether family screening is beneficial. Krahn et al. (31) performed a prospective study in 9 centers across Canada wherein patients with unexplained cardiac arrest and no evident cardiac disease underwent systematic evaluation including cardiac magnetic resonance imaging (MRI), signal-averaged ECG, exercise testing, drug challenge (including intravenous epinephrine and procainamide challenges), and selective invasive electrophysiological testing and/or endomyocardial biopsy. Early repolarization was defined as J-point elevation of at least 0.1 mV in at least 2 inferior or lateral leads. Over approximately 4 years, 63 patients with unexplained cardiac arrest were identified. All had an ejection fraction ≥50% and normal coronary arteries. None had overt evidence of a prolonged QT interval, arrhythmogenic right ventricular cardiomyopathy (ARVC), the Brugada syndrome, ST-segment elevation, evidence of hypertrophic cardiomyopathy on imaging, anomalous coronary arteries, had experienced commotio cordis, or had a regular wide complex tachycardia consistent with idiopathic VT. With the systematic testing, 35 patients (56%) received a specific diagnosis: long QT syndrome (LQTS) was diagnosed in 8 (23%), catecholaminergic polymorphic VT was diagnosed in 8 (23%), ARVC in 6 (17%), early repolarization in 5 (14%), coronary spasm in 4 (11%), Brugada syndrome in 3 (9%), and myocarditis in 1 (3%). Provocative testing had the highest yield of all the different components, with abnormal findings in 18 patients (29%). Subsequent targeted genetic testing was performed in 19 patients, and evidence of a causative mutation was found in 9 (47%) of these. Family screening of 64 family members of the 9 patients with causative mutations resulted in the discovery of mutations in 15 (24%), including 2 with LQTS, 4 with Brugada syndrome, and 9 with catecholaminergic polymorphic VT. Although the minority of those with resuscitated sudden death have no explanation, those somewhat rare patients are often young and otherwise healthy. In addition, that event may serve as a marker of risk in additional family members. This important paper provides a useful algorithm that can serve as a guide in evaluating these patients, potentially helping to guide the most appropriate therapy and focused genetic testing.

A wide array of important recent basic and translational observations bearing on clinical manifestations of disease processes have been described. This is especially true for the channels involved in the LQTS. Kapa et al. (32) described the results of an in-depth analysis of the types, frequency, and site of mutation for the 3 genes most associated with the LQTS, namely LQT1 (KCNQ1), LQT2 (KCNH2), and LQT3 (SCN5A). They compared the genetic structure of 388 “definite” LQTS cases with 1,300 healthy controls. Simple missense mutations (single amino acid substitutions) were found to be most common in LQTS cases as well as controls. They found, however, that simple missense mutation involving transmembrane, linker, or pore regions of KCNQ1 or KCNH2 were far more likely to correlate with disease state. In contrast, nonmissense mutations (i.e., frameshift, deletions, and so on) usually resulting in radical changes in channel structure were almost always associated with disease.

The discussion section of this work is especially helpful in emphasizing the clinical role of genetic resting. Such testing cannot be totally expected to result in a yes/no affirmation of disease in view of the “background” noise of rare missense mutations in the normal population. This study is very important in highlighting the correlation of both the type and site of mutation with high probabilistic indications of disease.

Another potentially important contribution to our understanding of the causes of variations in penetrance in the LQTS is provided by a study by Crotti et al. (33). The authors studied a homogenous type of KCNQ1 (A341V) segregating a founder (CK) mutation in South African families. They were able to study 500 subjects, 205 of whom were mutation carriers. The cohort was divided into those with severe symptoms (aborted sudden death or sudden death) compared with those with syncope.

The authors correlated both symptom severity as well as QT-interval duration with genetic variations in nitrous oxide synthetase adaptor protein (NOS1AP). This was chosen because prior studies in several large population studies showed that NOS1AP was associated with small quantitative increases in the QT interval (34- 35). In addition, this same gene has been associated with increased risk of death in a general population (36). The authors found a significant association with presence of symptoms and symptom severity, as well as greater likelihood of manifesting a QT interval, in the top 40% of mutation carriers.

Although the physiological link between NOS1AP and effects on the LQTS are speculative (37), nevertheless, the authors present impressive evidence for the role of NOS1AP as a genetic modifier in phenotypic expression of symptoms in a very homogenous LQTS population. This study breaks new ground in potentially explaining symptom severity in a specific LQTS population, and no doubt future studies will assess association of NOS1AP with other known genetic arrhythmia syndromes.

The adverse effects of hypokalemia in patients with either congenital or drug-induced LQTS are well established. The precise mechanism of these adverse effects is not clear. An important study by Guo et al. (38) addressed this issue using human embryonic kidney cells as well as in vivo rabbit studies. In a very detailed and meticulous study, they found that the rapid potassium delayed rectifier current membrane density of the I_Kr channel (KCNH2 gene) is controlled by the external K⁺ concentration. They showed that lowering the K⁺ concentration rapidly (overnight incubation in zero K⁺ concentration) accelerated the internalization and degradation of the I_Kr channels. This occurred in a K⁺ concentration-dependent fashion. However, hypokalemia produced no significant changes in Kv1.5 (Kur) and a modest reduction (30.3%) in KvLQT1 (I_Ks) current.

Further observations included studies of rabbits fed low K⁺ compared with those fed identical diets with K⁺. The hypokalemia rabbits showed a prolongation of both the QTc as well as action potential duration. They found that I_Kr expression was much lower in the hypokalemia group, but there was no significant changes in the L-type calcium current, inward rectifier current I_Kr, or the slow delayed rectifier current (I_ks). These unique observations demonstrate the critical role of hypokalemia in the regulation of the cell surface density of an ion channel and have important implications in the role of hypokalemia on the genesis of torsades.

An important study evaluating the structure and functional link between plakophilin-2 (PKP2) and sodium channel function is described by Sato et al. (39). Myocardial cells are joined by a specialized structure known as the intercalated disc. This region comprises proteins that provide mechanical support (desmosomes and adherens junctions) as well as gap junctions that allow for both metabolic and electrical connection between myocytes. PKP2 is a component of the desmosomes, and mutations in PKP2 have been linked to the clinical entity of ARVC.

The authors used monolayers of neonatal rat myocytes and observed coprecipitation of the alpha subunit of the sodium channel (Na_v 1.5) with PKP2. They showed that loss of expression of PKP2 had profound effects on the Na⁺ current in that both peak current Na⁺ was diminished as well as delayed recovery from inactivation. Both of these findings led to substantial decreases in Na⁺ current and conduction velocity. Importantly, they showed for the first time that loss of PKP2 expression led to conduction block and re-entrant arrhythmias.

Previous studies have shown that loss of PKP2 expression is associated with decreased connexin expression and cell-to-cell coupling (40). More recently, Asimaki et al. (41) demonstrated the high sensitivity and specificity of decreased plakoglobin staining for the diagnosis of ARVC. The current study further emphasizes the important link between intact desmosomal development and properties of cell-to-cell conduction and their role in the genesis of cardiac rhythm disorders (39).

Observations related to ion-channel subunit expression in Purkinje fibers (PFs) in congestive HF were reported by Maguy et al. (42). Recent basic and clinical observations highlighted the role of PFs in the genesis of cardiac arrhythmias, both in patients with and without structural cardiac disease (43- 44).

In this study, the authors set out to define changes in subunit mRNA and protein expression of ion channels and connexin in a dog model of congestive HF induced by rapid ventricular pacing. The major findings were down-regulation of proteins involved in conduction, namely the Na⁺ channel Nav1.5 (56%), connexin (Cx)40 (66%), and Cx43 (56%). They found decreased distribution of both Cx40 and Cx43 in the central intercalated disc region.

Electrophysiological studies showed no significant changes in the resting membrane potential or in action potential duration, but significant decreases in action potential amplitude as well as overshoot and phase zero upstroke in the PFs from the HF dogs. The His-Purkinje conduction velocity decreased, as manifested by a 39% increase in the H-V interval. These observations add further insight into the possible mechanisms of sudden cardiac death in the failing heart.

An intriguing paper by Lalani et al. (45) describes a new genetic abnormality associated with WPW patterns and musculoskeletal and neurocognitive defects. To date, although familial clustering of the WPW syndrome has been described, only 1 gene (PRKAG2) has been identified as being associated with WPW (46). The latter is due to distortion of the atrioventricular annulus by glycogen-filled myocytes that brings atrium and ventricle in continuity.

The syndrome described by Lalani et al. (45) involves a microdeletion of 20p12.3, with all patients showing involvement of a single gene (BMP2). Bone morphogenetic protein belongs to the class of proteins that includes transforming growth factor and is involved in the development of the atrioventricular canal. Selective deletion of proteins in this family has been shown to produce pre-excitation in mice (47). These observations point to the finding of only the second gene implicated in the WPW pattern.

The MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy) trial, sponsored by Boston Scientific, is a pivotal trial that may potentially expand the use of CRT devices in HF management. At the end of 2.4 years, when compared with an ICD alone, the use of a CRT device that includes defibrillation (CRT-D) significantly reduced all-cause mortality or HF events (primary composite end point) by 34% in asymptomatic or mild symptomatic (New York Heart Association [NYHA] functional class I and II for ischemic and class II for nonischemic dilated cardiomyopathy) patients with a left ventricular ejection fraction (LVEF) ≤30% and a QRS duration of 130 ms (48). These numbers would argue for an expanded indication for CRT-D to include the estimated millions of asymptomatic or mildly symptomatic patients with significantly reduced LVEF. However, further examination of the data raises the question of whether the risks of implanting a CRT-D device in patients with mild HF are worth the benefit in a wider patient population on the open market. There was no difference in mortality (3% annually); the effectiveness was driven by a 41% reduction in HF events (primarily in hospitalization rate) among patients with a QRS duration ≥150 ms and left bundle-branch block. CRT-D therapy was associated with more system-related complications. As a result, the proportion of patients experiencing complications from any cause (system-related and HF events) at any time was similar (60.4% in the CRT-D and 59.7% in the ICD group). Another question is whether the study patients were truly as healthy as typical real-world functional class I or II patients because 40% were previously hospitalized for HF and 10% were in NYHA functional class III or IV more than 3 months before enrollment. Even under these conditions, the study failed to show that NYHA functional class I patients benefited from CRT-D. Furthermore, this group of patients is more likely to have a very active lifestyle than class III or IV patients. Device complications are possibly higher, and living with a CRT-D may have a bigger negative impact on their quality of life and, consequently, on patient acceptance. The long-term impact on cardiac performance and mortality from shocks, appropriate or inappropriate, has yet to be ascertained. After considering some of these issues, the Circulatory System Devices Panel of the U.S. Food and Drug Administration recommended approval of CRT-D therapy to patients who met the MADIT-CRT enrollment criteria with an added requirement that these patients also have a left bundle-branch block.

The SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) data were reanalyzed using a previously established risk-predication model for HF (Seattle Heart Failure Model) (49). Patients were grouped into 5 quintiles of increasing annual mortality according to a set of clinical variables (age, sex, systolic blood pressure, ischemic etiology, LVEF, NYHA functional class, serum sodium and creatinine, and HF medications). The benefits of ICD therapy on all-cause mortality were related to the predicted risk quintile: the lowest risk quintile had a relative risk reduction of 54%, decreasing to 31% in the fourth quintile and zero in the highest risk quintile (predicted annual mortality >20%). The effect was driven by lack of an effect of ICD therapy on sudden cardiac death in the highest risk quintile. The analysis reconfirmed that comorbidities reduce the survival benefit of ICD therapy. The mode of death was analyzed in the SCD-HeFT patients in another study (50). ICD therapy had no effect on HF mortality. The reduction in overall mortality with ICD therapy was due exclusively to a reduction of sudden cardiac death, presumably due to ventricular tachyarrhythmia. This finding was similar to that in the MADIT-II analysis. Remarkably, there was no benefit of ICD therapy in reducing ventricular tachyarrhythmia death in NYHA functional class III patients, who were more likely to die from HF. However, in the absence of more data, the result of this subgroup analysis should not lead to exclusion of ICD therapy in NYHA functional class III patients.

The relationship between physician credentials and ICD implantation were evaluated using data from the American College of Cardiology-National Cardiovascular Data Registry (51). When compared with board-certified electrophysiologists, the incidence of ICD insertion complications was statistically higher among nonelectrophysiologist cardiologists (3.5% vs. 4.0%; relative risk: 1.11; 95% CI: 1.01 to 1.21). The vast majority of the implants were performed by electrophysiologists (71%), and nonelectrophysiologists were less likely to implant a CRT-D in eligible patients. Members of the electrophysiology community have long argued against nonelectrophysiologists implanting ICDs. But before electrophysiologists use the result as a mandate of exclusion, it is important to point out that the higher complication rate occurred only in dual-chamber ICD implantations. Remarkably, adding an atrial lead increased complication rates for both electrophysiologists and nonelectrophysiologists (2.1% and 3.1%, respectively, for single- and dual-chamber ICDs among electrophysiologists; 2.5% and 3.7%, respectively, among nonelectrophysiologists). But the absolute dual-chamber ICD complication rate for nonelectrophysiologists reached statistical significance when compared with electrophysiologists. Based on this analysis, an argument can be made for nonelectrophysiologists to limit their implantations to single-chamber ICDs. Because the majority of the implantations are for primary prevention (83% in this study), which requires a single-lead device as mandated by Centers for Medicare and Medicaid Services, nonelectrophysiologists can continue their role in improving access to ICD therapy. As pointed out in the accompanying editorial, factors other than skill sets and training may be involved in a lower CRT-D implant rate by nonelectrophysiologist cardiologists (52). One can argue that they are in a better position to consider confounding clinical factors that may lead to a decision not to implant a CRT-D.

The PACE (Pacing to Avoid Cardiac Enlargement) study revisited the superiority of biventricular pacing over right ventricular pacing (53). After 12 months of continuous pacing in patients with normal systolic function, right ventricular apical pacing reduced LVEF by 6.7 absolute percentage points (from 61.5 ± 6.6% to 54.8 ± 9.1%) and increased left ventricular end-systolic volume by 25% (from 28.6 ± 10.7 ml to 35.7 ± 16.3 ml), whereas biventricular pacing effected no changes. The number of patients in this study was small and the follow-up period was short, and more importantly, the reduction in the values of the selected end point parameters was not associated with any significant clinical differences. Taking into consideration the much higher complication rate associated with biventricular system implantation (not reported in the paper) and more frequent and higher cost of generator replacements due to high left ventricular output demand on the battery, this study did not offer any compelling reason for biventricular pacing at the time of implantation for all patients with normal ventricular function.

Despite the obvious evidence of the deleterious effects of right ventricular pacing in ICD patients with left ventricular systolic dysfunction in the DAVID (Dual Chamber and VVI Implantable Defibrillator) trial, the DAVID II trial was launched to confirm that the culprit was really “excessive” right ventricular pacing only (54). Accordingly, AAI pacing mode at a relatively high pacing rate of 70 beats/min was compared with VVI pacing at 40 beats/min. There were no significant differences in the combined end point of time to death or HF hospitalization between these 2 pacing modes during a mean follow-up of 2.7 years. The incidence of AF, syncope, shocks, and quality of life also did not show any differences. The findings are not surprising in view of the results of the DAVID trial. The issue is obviously not dual-chamber versus single-chamber ICD; it is a question of “excessive” RV pacing. The algorithm for programming can be surprisingly fundamental: avoid pacing if possible; if pacing is clinically required, use AAIR pacing (optimized to patients' physiological need) if possible.

The American Heart Association updated its clinical guideline on cardiovascular implantable electronic device infections and their management (55). The statement reported an increase in incidence of infection out of proportion to increased rates of new device implantation. Risk factors include diabetes mellitus, HF, generator replacement and renal insufficiency, oral anticoagulant and long-term corticosteroid use, presence of more than 2 pacing leads, fever within 24 h before implant, temporary pacing, and early reintervention. Complete removal of the device system is required to eradicate infection. Perioperative antimicrobial prophylaxis is the most effective way to lower infection. It also emphasizes that antibiotics prophylaxis for routine dental, gastrointestinal, and genitourinary procedures is not indicated in patients with these devices. Sonication of devices before culture allowed a group of investigators to show that bacteria colonize cardiac implantable electronic devices without clinical signs of infection (56). However, the clinical implication is unknown. Data collected from a single center showed that percutaneous lead extraction can be safely performed without thoracotomy in patients with right-sided infectious endocarditis with intracardiac vegetations (valvular and lead) by a team of very experienced operators (57).