Highlights of the Year in JACC 2010 FREE

As in past years, this Highlights article takes the place of the Editor's Page, and was assembled by the Associate Editors on the basis of the manuscripts that they perceived had or would have the greatest impact upon cardiology. Space constraints result in omitting many excellent manuscripts, and we apologize in advance to the authors.

Is the metric of door to balloon time (DBT) of great importance in patients who present late in the course of their STEMI? Theoretically, with less muscle to salvage, late presentations may negate the benefit of a short DBT. Using data from the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) and the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trials, Brodie et al. (1) document that in the subgroup of patients with late presentations (>90 min from onset of pain), long DBT was no longer associated with a lower mortality. Both high-risk and low-risk patients in the early presentation group benefited from a short DBT, but the absolute benefit was greatest in the high-risk patients (3.7% vs. 7.0% for short DBT vs. long DBT) compared with low-risk patients (0.8% vs. 1.5%).

One approach to reduce treatment delays is to initiate therapy in the pre-hospital setting. The On-TIME 2 (Ongoing Tirofiban in Myocardial Infarction Evaluation 2) trial evaluated the use of high-dose glycoprotein IIb/IIIA inhibitor tirofiban in the ambulance (2). The trial had an open label phase 1 followed by a double-blind phase 2; the primary endpoint of the pooled analysis was death, recurrent myocardial infarction (MI), and urgent target vessel revascularization (TVR) at 30 days. During the 3 years of the trial, 1,398 patients were treated, 414 in the open label phase and 984 in the double-blind phase. Major adverse cardiac events (MACE) at 30 days were significantly reduced by high-dose tirofiban (5.8% vs. 8.6%, p = 0.043) with a trend toward a reduction in mortality (2.25% vs. 4.1%, p = 0.051). There was no increase in bleeding noted.

While pre-hospital administration of lytics and adjunct therapies may improve time to reperfusion, patient delays in calling 911 still average more than 2 h. A novel approach to reduce this delay was reported by Fischell et al. (3), who implanted an intracardiac ST-segment monitoring device in 37 patients who were at high risk for acute coronary syndromes. The implanted device, similar to a pacemaker, continuously monitored the ST segments from the right ventricular apical lead. Patients were alerted with an alarm when ST-segment elevations were noted of 3 SDs or more of their regular daily range. Over a median follow-up of 1.52 years, 4 patients had appropriate alarms, which led to very rapid presentation to the hospital of 19.5 min. An additional 4 patients had alarms at elevated heart rates, which were determined to be related to flow-limiting lesions. Three patients had false positive alarms. This novel approach may be practical in patients already receiving a pacemaker/defibrillator.

Since bleeding during treatment of acute coronary syndrome (ACS), primarily invasive treatment, is a significant risk factor for mortality, it is important to predict the risk of this complication. Using data from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy Trial) and the HORIZONS-AMI trials, Mehran et al. (4) developed a simple 7-variable risk score consisting of female sex, advanced age, elevated serum creatinine and white cell count, anemia, non-STEMI, or STEMI, as well as the use of heparin plus a IIb/IIIa inhibitor. Moreover, the risk score identified patients at risk not only for 30-day rate of non–CABG-related major bleeding but also 1-year mortality. The score ranged from 0 (0.9% risk of major bleeding within 30 days) to 40 (43.5% bleeding risk). The risk score may allow for tailoring percutaneous coronary intervention (PCI) procedures (such as with the use of radial approach rather than femoral approach) to lower the bleeding risk. Whether such an approach would reduce mortality remains to be proven.

Optimal assessment of cardiovascular (CV) risk continues to be controversial. Where different studies have reached varying conclusions such as metabolic syndrome, the use of meta-analysis may be helpful. Mottillo et al. (5) performed a meta-analysis of 87 studies, involving 951,083 patients (approximately one-half using the 2001 National Cholesterol Education Program definition and half using the 2004 revised definition for the metabolic syndrome). The metabolic syndrome was found to be associated with a relative risk of 2.35 for CV disease, 2.02 for CV disease mortality, 1.58 for total mortality, 2.99 for MI, and 2.27 for stroke risk. Whether the risk associated with the metabolic syndrome is greater than the sum of its parts remains unclear.

Abdominal obesity is a key component of the metabolic syndrome. The question of whether a modest increase in abdominal fat is deleterious was assessed by Romero-Corral et al. (6) using the surrogate endpoint of endothelial dysfunction. They recruited 43 normal weight and healthy volunteers who were then randomly assigned to a weight gain group. Endothelial function measured by flow-mediated dilation decreased (9.1 ± 3% vs. 7.8 ± 3.2%, p = 0.003) with an average weight gain of 4.1 kg, but recovered when the subjects lost the weight again.

While low-density lipoprotein (LDL) cholesterol has been the primary lipid risk factor and target of therapy in various guidelines, increasing attention has been paid to other lipid parameters. Non–high-density lipoprotein (HDL) cholesterol is an attractive measure and target as it quantifies the cholesterol in all the known atherogenic cholesterol particles, including very low-density lipoprotein (VLDL), intermediate-density lipoprotein, and chylomicron remnants. Arsenault et al. (7) reported 21,488 men and women without diabetes mellitus or coronary disease between the ages of 45 and 79 years followed up for 11 years in the European Prospective Investigation Into Cancer and Nutrition-Norfolk population study. Even among subjects with low LDL cholesterol levels (<100 mg/dl), an elevated non-HDL cholesterol >130 mg/dl was associated with a hazard ratio (HR) of 1.84 compared with non-HDL cholesterol <130 mg/dl. Total cholesterol/HDL cholesterol and elevated triglycerides were also associated with increased risk.

Moderate alcohol consumption has been shown to be associated with reduced CV and overall mortality. Whether alcohol consumption has similar associations in secondary prevention populations is less clear. Costanzo et al. (8) performed a meta-analysis of 8 selected studies, which included 16,351 patients. They found that in a secondary prevention population there was a J curve with maximal protection for CV mortality by consuming 26 g/day, with a lower consumption in the range of 5 to 10 g/day having the lowest overall mortality.

The use of imaging to identify asymptomatic atherosclerosis and further risk stratify patients evaluated for primary prevention continues to generate intense interest as well as debate (9- 10). Nambi et al. (11), reporting on data from the ARIC (Atherosclerosis Risk In Communities) study, assessed whether carotid intima-media thickness (CIMT) and carotid plaque, alone or in combination, improved risk stratification based on traditional coronary heart disease (CHD) risk factors. Of 13,145 subjects, close to a one-quarter were reclassified by adding CIMT plus plaque information, with an improvement in the area under the curve from 0.742 to 0.755. The net reclassification index was highest at 9.9% when both the CIMT and presence of plaque were added to the traditional CHD risk factors. The findings of the study add to an increasing body of literature supporting the incorporation of carotid imaging in intermediate risk patients, and are particularly timely given the upcoming National Cholesterol Education Program Adult Treatment Panel IV report (12).

While carotid imaging with intima media thickness (IMT) may play a role in baseline risk assessment, it has also been proposed as a surrogate endpoint for CV events in various intervention trials such as lipid-lowering therapy. Costanzo et al. (13), therefore, performed a meta regression analysis of randomized trials assessing IMT regression with reduction in CV effects. They included 41 trials enrolling 18,307 participants. Despite significant reduction in CV events and all-cause death with active treatments, surprisingly there was no significant relationship between IMT regression and CHD events. These findings raise doubt as to the suitability of IMT regression as a surrogate endpoint in CV trials.

Endothelial dysfunction is an early event in the progression of atherosclerosis, and therefore may also have a role in risk stratification. The traditional modality of brachial artery reactivity (flow-mediated dilation [FMD]) is technically challenging, however, and has not gained routine clinical use. Matsuzawa et al. (14), used a simpler and less user-operated commercial device, the Endopat 2000 (Itamar, Cesarea, Israel), which utilizes a finger plethysmograph rather than ultrasound measurement of the brachial artery. The reactive hyperemia peripheral artery tonometry (RH-PAT) measured by the device has been shown to correlate with FMD and with coronary endothelial dysfunction, and impaired RH-PAT was predictive of ischemic events in women. They further found that compared with the Reynolds Risk Score, RH-PAT was more predictive for nonobstructive coronary artery disease (CAD).

While smoking has been well recognized as a potent CV risk factor for decades, the impact of secondhand smoke (SHS) has been less well defined, and the associated mechanisms have not been fully understood. Hamer et al. (15) studied 13,443 subjects in England and Scotland and measured salivary cotinine, an objective marker of exposure to SHS. Exposure to SHS was associated with all-cause mortality (HR: 1.21) and elevated C-reactive protein (CRP), linking inflammation as a mediator of SHS-related CV disease. Not all studies on smoking have confirmed an association with CRP. In a study from Japan, Tomiyama et al. (16) studied 2,054 subjects who were divided by their smoking status. Over a 5- to 6-year follow-up period, the continuous heavy smokers had significantly greater progression of arterial stiffening as judged by brachial-ankle pulse wave velocity. There was no relationship found, however, in that study with serum CRP levels.

The benefits of smoking cessation on vascular function was assessed by Johnson et al. (17) in a study of 1,504 smokers enrolled in various smoking cessation therapies. Among those who successfully quit smoking (36.2% of the cohort), there was a 1% improvement in FMD (6.2 ± 4.4% to 7.2± 4.2%), whereas those who continued smoking had no change in FMD.

While statins are likely to remain the cornerstone of lipid-lowering therapy, attempts to develop novel antilipidemic drugs continue. One approach is to inhibit the production of apolipoprotein B (apo-B), the carrier protein of atherogenic particles such as LDL. Akdim et al. (18) reported on the efficacy and safety of mipomersen, an antisense inhibitor of apo-B synthesis. In their phase 2 dose-escalation study, 74 subjects were enrolled into 6 dose cohorts, from 30 to 400 mg. The LDL cholesterol and apo-B were reduced by up to 52% and 54%, respectively. The drug, which is injected once weekly, caused some mild to moderate erythema. Importantly, there was a very high (50%) incidence of liver enzyme elevation in a group given the drug for 13 weeks.

The safety of statins, and particularly whether they may pose a cancer risk, has been the subject of much investigation and debate. Important additional data in this area were added by Gränsbo et al. (19), using a Swedish acute MI registry, with data on 21,410 patients 80 years of age and older. Using propensity analysis, they demonstrated a significant reduction in all-cause mortality without any increase in cancer mortality. These data are particularly interesting as it points to the benefit of statin treatment without increased cancer mortality in an elderly population with a high risk of cancer.

The role of platelets in acute coronary syndromes and post-PCI complications as well as the complex area of response to clopidogrel and its interactions with other drugs (and the contribution of polymorphisms to these interactions) continued to generate great interest in 2010.

Whether a rebound phenomenon exists upon cessation of clopidogrel is a key question, as guidelines suggest discontinuing clopidogrel after 1 year of therapy after DES. Sibbing et al. (20) randomly assigned 65 patients about to have clopidogrel stopped to either a tapering regimen or abrupt discontinuation. The authors measured platelet aggregation using light transmission aggregometry and multiple electrode aggregometry. Adenosine diphosphate (ADP)-induced platelet aggregation was no different between the abrupt cessation and the tapering group, suggesting that rebound did not exist.

Lev et al. (21) identified 30 patients (of 485 initially screened) receiving 75 to 182 mg daily who were “aspirin resistant” and randomly allocated them to either 325 mg of aspirin or to the addition of omega-3 fatty acids. The patients were retested after 30 days. They found significant reductions in arachidonic acid and ADP-induced aggregation as well as in the VerifyNow score in both groups, with the majority in both groups no longer being aspirin resistant. Gajos et al. (22) similarly studied the effect of omega-3 fatty acids on platelet activation in patients on dual antiplatelet agents (aspirin and clopidogrel) undergoing PCI. After 1 month of treatment, platelet reactivity as assessed by 20 μmol/l ADP was reduced by 13.3% (p = 0.026).

One of the limitations of clopidogrel is that the drug is a prodrug, which requires activation through the cytochrome p450 system (CYP2C19) and is prone to polymorphisms. Prasugrel, while also a prodrug is more efficiently metabolized and produces greater, more rapid platelet inhibition, and reduced ischemic events but at an increased risk of bleeding. The pharmacodynamics of switching patients from clopidogrel to prasugrel was assessed in the SWAP (Switching Antiplatelet) study (23). The 139 patients with a recent ACS event were first treated with open label clopidogrel for 10 to 14 days, and were then randomly assigned to continued clopidogrel, prasugrel loading followed by maintenance prasugrel, or prasugrel maintenance only without a loading dose. Overall, prasugrel was more effective in achieving platelet inhibition than clopidogrel—the added platelet inhibition was evident at 1 week without a loading dose of prasugrel and within 2 h with a loading dose.

In ACS patients undergoing diagnostic angiography deemed to require coronary surgery, prior clopidogrel treatment may increase bleeding risk, prompting many surgeons to delay surgery for several days. Shim et al. (24) studied the use of a modified thromboelastography in predicting bleeding and need for transfusion in 100 recipients of clopidogrel awaiting coronary artery bypass graft surgery (CABG) within 5 days since their last dose of clopidogrel. They report that irrespective of time from last clopidogrel administration, high levels of platelet inhibition predicted increased blood loss and transfusion requirement after off-pump CABG, with a cut-off value of 70% for increased risk of transfusion. The use of the thromboelastography test may allow tailored timing of surgery to minimize bleeding risk and surgical delay.

Once a patient undergoes CABG is there a role for clopidogrel therapy? Gao et al. (25) randomly allocated 249 consecutive elective CABG patients to aspirin alone or to aspirin and clopidogrel therapy after CABG. Multislice coronary angiography was performed at 3 months. Vein graft patency was greater (91.6%) in the aspirin and clopidogrel group than in the aspirin-alone group (85.7%, p = 0.043). Longer-term studies are now needed.

Assessment of high risk for CABG remains challenging. While frailty is a well-recognized risk factor for poor outcomes, its objective assessment is difficult. Afilalo et al. (26) conducted a multicenter prospective study of 131 elderly patients undergoing coronary bypass surgery and/or valve replacement. They tested the predictive value of slow gait speed, defined as a time taken to walk 5 m of ≥6 s. The primary endpoint was a composite of in-hospital postoperative mortality or major morbidity. Slow gait speed was an independent predictor of the composite endpoint even after adjusting for the Society of Thoracic Surgeons risk score (odds ratio [OR]: 3.05).

Pre-hypertension, defined as 120 to 139 systolic or 80 to 89 mm Hg diastolic, is common and increases with age. Whether changes in body composition, namely, weight gain or weight loss as well as fat gain or loss, influence the progression or regression of hypertension in pre-hypertensive persons was examined by Markus et al. (27) in a cohort of 1,145 subjects from the MONICA/KORA (Monitoring Trends and Determinants on Cardiovascular Diseases/Cooperative Research in the Region of Augsburg) cohort study. They followed up the group over 10 years. Subjects who had progression to hypertension (one-half the cohort) were characterized by weight gain, principally due to fat gain, while the small percentage (6.76%) who went from being hypertensive to pre-hypertensive were characterized by decrease in body weight and fat mass.

Resistant hypertension is a vexing problem in clinical care. Scheffers et al. (28) report on the use of a novel implantable device (Rheos System, CVRx, Inc., Minneapolis, Minnesota) that works by electrical stimulation of the carotid sinus, thereby causing baroreflex activation. Studying 45 patients with resistant hypertension, they report a reduction in mean blood pressure of 21/12 mm Hg at 3 months. Although the study was not randomized, when the device was turned off, there was a prompt increase in blood pressure. Further study is clearly warranted for such nonpharmacologic approaches, which may be practical for the most difficult to treat patients.

Various publications over the past year assessed the contribution of arterial stiffness to the prediction of CV events, as well as the utility of the various measurements reflective of arterial stiffness.

Vlachopoulos et al. (29) performed a systematic review and meta-analysis of studies looking at the predictive value of aortic pulse wave velocity (PWV) for CV events and all-cause mortality. Using data from 17 studies (total of 15,877 subjects followed up for a mean of 7.7 years), they showed that the pooled relative risks (RR) for clinical events increased in a linear fashion across tertiles of PWV, including an almost doubling of risk of total mortality. An increase of 1 SD in aortic PWV was associated with an increase in total CV events, CV mortality, and all-cause mortality of 47%, 47%, and 42%, respectively.

Benetos et al. (30) reported on a novel hemodynamic biomarker for CV risk, which they termed pulse pressure amplification. Normally central (carotid) pulse pressure is lower than brachial blood pressure. With aging, there is a disproportionate increase in central aortic stiffness, which puts an increased load on the heart. The result is an increase in central pulse pressure amplification compared with brachial. This parameter can be quantified as the carotid/brachial ratio. The authors first derived a normogram relating measured brachial and carotid pulse pressure. They then applied this model to a population of 125,151 subjects who were followed up for 12 years. They found that the carotid/brachial ratio was a strong predictor for both CV and total mortality (HR: 1.22, 95% confidence interval [CI]: 1.12 to 1.32, and HR: 1.41, 95% CI: 1.14 to 1.73, respectively).

Widely accepted therapies such as antiplatelet agents and statins may have different risk/benefit profiles in patients with chronic kidney disease (CKD). One potentially novel mechanism was reported by Meyer et al. (31), who examined endothelial function in 14 hemodialysis patients. They measured FMD before and after dialysis and demonstrated a post-dialysis impairment of endothelial function, which correlated with release of hemoglobin (hemolysis). Moreover, the cell free hemoglobin led to a decrease in the bioavailability of free nitric oxide.

Jardine et al. (32) examined the effects of aspirin 75 mg daily versus placebo in patients with diastolic hypertension in the HOT (Hypertension Optimal Treatment) study who were stratified by glomerular filtration rate (GFR). The authors found an increasing benefit of aspirin treatment with decreasing renal function. Major CV events were reduced by 9%, 15%, and 66% in patients with baseline estimated GFR of ≥60, 45 to 59, and <45 ml/min/1.73 m² (p trend = 0.03); total mortality was similarly lowered, and major bleeding was nonsignificantly greater with lower eGFR. For every 1,000 patients with estimated GFR <45 ml/min/1.73 m² treated for 3.8 years, aspirin at 75 mg daily prevented 76 major CV events and 54 deaths, with only 27 excess major bleeds.

Diabetes and CKD often coexist. Diabetes is also a risk factor for high post-treatment platelet reactivity. Angiolillo et al. (33) examined 306 diabetic patients and compared the antiplatelet effects of dual antiplatelet therapy (aspirin and clopidogrel) in those with moderate and severe kidney dysfunction to those with normal kidney function. Patients with moderate/severe kidney disease were 3.8 times more likely to have high post-treatment platelet reactivity than were patients with normal function.

The long-term results of several landmark clinical trials regarding the treatment of ACS were reported this year. Damman et al. (34) reported the 5-year clinical outcomes of the ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes) trial. They randomly allocated 1,200 patients to an early invasive or selective invasive strategy. At 5 years, cumulative death and MI rates were 22.3% and 18.1% in the early invasive and selective invasive groups, respectively (p = 0.053). However, no statistically significant differences were observed in either mortality or MI. Thus, at 5 years, patients with non–ST-segment elevation ACS and elevated troponin T did not manifest a long-term benefit from an early invasive strategy in reducing either death or MI. In an accompanying editorial, Bittl and Maron (35) point out that most patients in either arm underwent diagnostic angiography. They further opine that both early invasive and delayed selective invasive strategies have values and limitations; the greatest importance of the ICTUS trial is that it demonstrates that an individualized approach can be undertaken in patients with non-STEMI.

In a related paper dealing with the issue of non-STEMI, Fox et al. (36) performed an interesting meta-analysis that incorporated the findings not only of the ICTUS trial, but also the 5-year outcomes from the FRISC2 (Fragment and Fast Revascularization During Instability in Coronary Artery Disease) trial and the RITA3 randomized trial of the conservative treatment strategy versus an interventional treatment strategy for patients with unstable angina. The inclusion of 5,467 patients rendered significant as statistical power. Over 5 years, 14.7% of the patients randomly assigned to a routine invasive strategy experienced either CV death or nonfatal MI versus 17.9% in the selective invasive arm (p < 0.002). The greatest effect was upon a MI, and there was a substantial benefit attributed to patients in the highest risk category. Thus, when the results of the ICTUS trial was combined with those of 2 other similar studies, a routine invasive strategy appeared superior, although this was most dramatic in the highest-risk patients.

The role of plaque instability and thrombus formation in the production of MI continues to evolve. Kramer et al. (37) studied coronary lesions from 111 sudden death victims from the medical examiner. In this group, 65 of the lesions were ruptures, whereas 50 were erosions. Interestingly, 69% of all lesions associated with sudden death were found to have “late stage” organizing thrombi. These data suggest the sudden death may actually be a late stage complication of plaque instability and thrombosis, and perhaps may be related to microembolization. In an accompanying editorial, Levin (37a) comments that the distinction of plaque erosion and plaque rupture may allow for individualized therapy in patients with CAD.

The JETSTENT(AngioJet Rheolytic Thrombectomy Before Direct Infarct Artery Stenting in Patients Undergoing Primary PCI for Acute MI) trial (38), a multicenter, prospective study compared rheolytic thrombectomy before direct infarct artery stenting to direct stenting to improve myocardial reperfusion and MACE in 501 acute MI (AMI) patients with angiographic evidence of thrombus grade 3 to 5 and a reference vessel diameter ≥2.5 mm. Co-primary endpoints were early ST-segment resolution and 99mTc-sestamibi infarct size (p < 0.05 for both or p < 0.025 for 1 for significance). The ST-segment resolution was more frequent in the rheolytic thrombectomy versus the direct stenting alone arm (85.8% vs. 78.8%, p = 0.043). Although no differences were noted in the other surrogate endpoints, the 6-month MACE rate (11.2% vs. 19.4%, p = 0.011) and 1-year event-free survival rates (85.2 vs. 75.0, p = 0.009) were improved with rheolytic thrombectomy. The authors suggest that, although the primary efficacy endpoints were not met, the results support the use of rheolytic thrombectomy before infarct artery stenting in patients with AMI and evidence of coronary thrombus. However, an accompanying editorial suggested that in keeping with current guideline recommendations, thrombus extraction seems to be a useful adjunctive therapy for patients undergoing primary PCI for STEMI, and the modality of choice appears to be simple manual aspiration (39).

The ZEST (Comparison of the Efficacy and the Safety of Zotarolimus-Eluting Stent Versus Sirolimus-Eluting Stent and Paclitaxel-Eluting Stent for Coronary Lesions) trial (40), a single-blind, multicenter, prospectively randomized trial involving 2,645 patients undergoing PCI evaluated the relative efficacy and safety of zotarolimus-eluting stents (ZES), sirolimus-eluting stents (SES), and paclitaxel-eluting stents (PES) for a composite of MACE at 12 months. At 12 months, the ZES group showed noninferior rates of MACE compared with the SES group (10.2% vs. 8.3%, p for noninferiority = 0.01, p for superiority = 0.17) and significantly fewer MACE than the PES group (10.2% vs. 14.1%, p for superiority = 0.01). The incidence of death or MI was similar among the groups. The incidence of stent thrombosis was significantly lower in the SES group (ZES vs. SES vs. PES, 0.7% vs. 0% vs. 0.8%, respectively; p = 0.02). In this large-scale, practical randomized trial, the use of ZES resulted in similar rates of MACE compared with SES, and fewer MACE compared with PES at 12 months.

The EVA-AMI (Efficacy of Eptifibatide Compared With Abciximab in Primary PCI for Acute ST Elevation MI) trial (41) randomly allocated 427 patients with STEMI <12 h and planned primary PCI to double-bolus eptifibatide followed by a 24-h infusion or single-bolus abciximab followed by a 12-h infusion. In this noninferiority trial, the primary endpoint was the incidence of complete (≥70%) ST-segment resolution 60 min after PCI. The incidence of complete ST-segment resolution at 60 min after PCI in the intention-to-treat analysis was 62.6% after eptifibatide and 56.3% after abciximab, and reinfarction was 0.4% versus 3.5%, respectively (p = 0.03). All-cause mortality, the combined endpoint of death, nonfatal reinfarction, TVR, after 6 months, and major bleeding complications after 30 days were similar. In conclusion, eptifibatide as an adjunct to primary PCI is equally as effective as abciximab with respect to ST-segment resolution.

In the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) study (42), 11,479 STEMI patients who underwent primary PCI and received either eptifibatide or abciximab were evaluated for the primary endpoint of death or MI during 1-year follow-up, with adjustment for baseline differences with a multivariate logistic regression analysis including propensity score. The combined endpoint occurred in 15% treated with eptifibatide and 15.7% treated with abciximab, the unadjusted OR was 0.95 (95% CI: 0.84 to 1.08). Multivariate adjustment and the adjusted secondary endpoints of death and MI separately also showed noninferiority. This large registry also supports that eptifibatide is noninferior to abciximab for patients with STEMI undergoing primary PCI.

The ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) trial (43), randomly allocated, open-label, 450 patients with clinically significant in-SES restenosis to repeat SES versus PES. The primary endpoint was late lumen loss based on in-stent analysis at 6- to 8-month follow-up angiography. There were no differences between SES and PES in late loss, binary restenosis, target lesion revascularization (TLR), death/MI, and stent thrombosis, suggesting a comparable degree of efficacy and safety.

The ENDEAVOR IV (Randomized Comparison of Zotarolimus-Eluting and Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease IV) trial (44) evaluated the safety and efficacy of ZES (n = 773) compared with PES (n = 775) in a prospective, randomized, single-blind, controlled trial in patients with single de novo coronary lesions. The primary endpoint was noninferiority of 9-month target vessel failure (TVF) defined as cardiac death, MI, or TVR. At 9 months, ZES was noninferior to PES regarding TVF, and fewer had periprocedural MIs (0.5% vs. 2.2%; p = 0.007), although at 12 months there were no significant differences between groups in rates of cardiac death, MI, TVR, or stent thrombosis.

The LIPSIA-N-ACC (Myocardial Salvage and Contrast Dye Induced Nephropathy Reduction by N-Acetylcysteine) trial (45), a randomized, single-blind, controlled trial assessed N-acetylcysteine effects on contrast-induced nephropathy and reperfusion injury in 251 STEMI patients undergoing primary PCI with moderate contrast volumes. Patients were randomly allocated to either high-dose N-acetylcysteine (2 × 1,200 mg daily for 48 h) or placebo plus optimal hydration. The 2 primary endpoints were: 1) the occurrence of >25% increase in serum creatinine level <72 h after randomization; and 2) a reduction in reperfusion injury measured as myocardial salvage index by magnetic resonance imaging. The primary endpoint occurred in 14% of the N-acetylcysteine group and in 20% of the placebo group (p = 0.28). The myocardial salvage index was also not different. High-dose intravenous N-acetylcysteine does not provide an additional clinical benefit to placebo in nonselected patients undergoing PCI, although a larger study with more power may be indicated to define the role of N-acetylcysteine in PCI.

The NORDISTEMI (Norwegian Study on District Treatment of ST-Elevation MI) trial (46) compared immediate transfer for PCI with an ischemia-guided approach after thrombolysis in patients with very long transfer distances. A total of 266 patients with STEMI with >90-min transfer delays for PCI were treated with tenecteplase, aspirin, enoxaparin, and clopidogrel and randomly assigned to immediate transfer or to standard management in the local hospitals except clinical deterioration. The primary outcome, a composite of death, reinfarction, stroke, or new ischemia at 12 months, was reached in 21% patients in the early invasive group compared with 27% in the conservative group. (p = 0.19). The composite of death, reinfarction, or stroke at 12 months was significantly reduced in the early invasive compared with the conservative group (6% vs. 16%, p = 0.01). No significant differences in bleeding or infarct size were observed, perhaps because of the high rate of radial access (>80%). In conclusion, immediate transfer for PCI reduced the rate of death, reinfarction, or stroke at 12 months among patients with STEMI treated with thrombolysis and clopidogrel in areas with long transfer distances.

The ARMYDA-5 PRELOAD (Antiplatelet therapy for Reduction of Myocardial Damage During Angioplasty) randomized trial (47) evaluated the safety and effectiveness of 600 mg clopidogrel in laboratory loading before PCI (in-laboratory, n = 205) versus 600 mg given 4 to 8 h before PCI (pre-load, n = 204). The primary endpoint, 30-day incidence of MACE, was similar between groups (8.8% in-laboratory vs. 10.3% pre-load), and no difference in bleeding or vascular complications was observed. Thus, when indicated, in-laboratory clopidogrel administration before PCI can be a safe alternative to routine pre-treatment given before knowing patients' coronary anatomy.

The FAME (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation) study (48) investigated the relationship between angiographic and functional severity of coronary artery stenoses in 509 patients with multivessel CAD in the fractional flow reserve (FFR)-guided arm of the FAME study. Before FFR measurement, these lesions were categorized into 50% to 70% diameter stenosis (47% of all lesions), 71% to 90% diameter stenosis (39% of all lesions), and 91% to 99% diameter stenosis (15% of all lesions) by visual assessment. A total of 35%, 80%, and 96% stenosis were functionally significant (FFR ≤0.80) in the category 50% to 70%, 71% to 90%, and 90% to 91%, respectively. In stenoses, 96% were functionally significant. Of all 509 patients with angiographically defined multivessel disease, only 46% had functional multivessel disease by FFR. This study suggests that angiography is inaccurate in assessing the functional significance of a coronary stenoses in the 50% to 90% range.

The principle investigators of the FAME trial also reported their 2-year follow-up results comparing FFR versus angiography to guide PCI in patients with multivessel CAD (49). Combined rates of death and MI were 12.9% in the angiography-guided group and 8.4% in the FFR-guided group (p = 0.02). Differences between these approaches were not statistically significant when revascularization was added. Thus, these data indicate that routine measurement of FFR in patients with multivessel CAD undergoing PCI with drug-eluting stents reduces mortality and MI at 2 years compared with a standard angiography-guided PCI.

The DEDICATION (Drug Elution and Distal Protection in ST Elevation MI) trial (50) evaluated the long-term effects of distal protection during PCI for STEMI patients assigned to distal protection (n = 312) or conventional treatment (n = 314). The total number of stent thromboses was 11 in the distal protection group and 4 in the conventional treatment group (p = 0.06). In primary PCI for STEMI, the routine use of distal protection increased the incidence of definite stent thrombosis and clinically driven TLR/TVR during 15 months of follow-up. Although the events rates are low and the study needs to be confirmed, the results does suggest that additional vessel manipulation by distal protection devices may lead to increased MACE in native coronary vessels.

The SESAMI (Sirolimus-Eluting Stent Versus Bare-Metal Stent In Acute MI) trial (51) investigated whether the reported favorable 1-year MACE incidence of SES versus BMS in 320 STEMI patients was maintained at 3-year follow-up. The 3-year incidence of MACE was lower in the SES group compared with the BMS group (12.7% vs. 21%, p = 0.034), as were TLR, TVR, and TVF rates. The 3-year survival rate free from MACE, TLR, and TVF was significantly higher in the SES group than in the BMS group. The lower incidence of adverse events in the SES group was driven by TLR reduction and achieved in the first year of follow-up. The cumulative incidence of death and recurrent MI, starting from clopidogrel discontinuation, was comparable in the 2 groups.

The ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial (52) evaluated the impact of delay to PCI in 7,749 patients with non–ST-segment elevation ACS at a median of 19.5 h after presentation. Delay to PCI >24 h after clinical presentation was significantly associated with increased 30-day mortality, MI, and composite ischemia (death, MI, and unplanned revascularization). By multivariable analysis, delay to PCI of >24 h was a significant independent predictor of 30-day and 1-year mortality, and risk was greatest for high-risk patients. These findings suggest that angiography and triage to revascularization within 24 h should be a priority in non–ST-segment elevation ACS patients.

The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus And Cardiac Surgery) trial in patients with symptomatic left main and/or 3-vessel disease demonstrated that bypass surgery and percutaneous intervention with Taxus stents yielded comparable results for death and MI, but a higher stroke rate for surgery and higher repeat revascularization rate for PCI. Banning et al. (53) reported the results of the Taxus trial in the pre-specified subgroup with diabetes mellitus. In 452 patients with diabetes, the 1-year major adverse cardiac and cerebral vascular event rate was higher when treated with paclitaxel stents than with bypass surgery, a difference due to a greater rate of repeat revascularization. However, the rate of hard events (death, MI, or stroke), was similar for the 2 treatment approaches. In an accompanying editorial, Dauerman (54) opines that these results indicate that, in diabetic patients with left main or triple-vessel disease, PCI with paclitaxel-eluting stents is not associated with increased mortality, as was true of bare metal stents, and may be undertaken in patients judged to be poor candidates for bypass surgery.

The HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial randomly assigned >3,000 patients with STEMI to either paclitaxel-eluting stents or BMS (55). At 24 months of follow-up, TLR continued to be less with the PES than with BMS. Importantly, insulin-treated diabetes, reference vessel diameter <3.0 mm, and lesion length >30 mm were independent predictors of 12-month TLR with BMS. In patients with 2 or 3 of these risk factors, PES markedly reduced 12-month TLR, but no difference between PES and BMS existed for patients with no risk factors. Thus, in patients with STEMI, PES is of benefit in reducing TLR in patients with risk factors, but not in lower risk patients.

Byrne et al. (56) reported the 2-year clinical and angiographic outcomes of the ISAR-TEST-2 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents) trial. In a randomized trial, they compared sirolimus, a new generation sirolimus and probucol-eluting stent, with zotarolimus-eluting stent (56). Probucol was added to sirolimus to target a different element of the restenotic process well as to retard the release of the sirolimus by virtue of lipophilicity. At 2-year follow-up, the drugs were found to have comparable safety profiles whereas the dual sirolimus/probucol stent manifested a greater reduction of TLR than the sirolimus stent, but comparable to that of the Endeavor instrument.

The MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) registry (57) evaluated 2,240 patients with unprotected left main coronary artery disease who received coronary stents (n = 1,102; 318 with BMS) or underwent CABG (n = 1,138) between 2000 and 2006, and for whom complete follow-up data were available for at least 3 to 9 years (median 5.2 years). After adjustment for differences in baseline risk factors with the inverse probability of treatment weighting, the 5-year risk of death (HR: 1.13; p = 0.35) and the combined risk of death, Q-wave MI, or stroke (HR: 1.07; p = 0.59) were not significantly different. The risk of TVR was significantly higher in the stenting group than in the CABG group (HR: 5.11; p < 0.001). Similar results were obtained in comparisons of BMS with concurrent CABG and of DES with concurrent CABG.

The ASAN-MAIN (ASAN Medical Center–Left Main Revascularization) registry (58) evaluated the long-term safety and effectiveness of PCI compared with CABG for unprotected left main coronary artery disease in a 10-year clinical follow-up of 350 patients who underwent PCI with BMS or CABG (n = 250) and 5-year clinical follow-up of 395 patients with DES or CABG (n = 219). In the 10-year follow-up cohort of BMS and concurrent CABG, the adjusted risks of death and the composite of death, Q-wave MI, or stroke were similar between the 2 groups. The rate of TVR was significantly higher in the group that received BMS (HR: 10.34; p < 0.001). In the 5-year follow-up cohort of DES and concurrent CABG, there was no significant difference in the adjusted risk of death or the composite outcome. The rates of TVR were also higher in the DES group than the CABG group (HR: 6.22; p < 0.001). This registry of long-term outcomes of unprotected left main coronary artery disease suggests that PCI with stent implantation is associated with similar long-term mortality and rates of death, Q-wave MI, or stroke but higher rates of repeat revascularization than CABG for both BMS and DES.

The ARTS II (Arterial Revascularization Therapies Study II) study (59) compared the 5-year clinical outcomes, safety, and efficacy of SES with the outcomes of CABG and BMS from the ARTS I study. The ARTS I study was a randomized trial of 1,205 patients with multivessel disease comparing CABG and BMS. The ARTS II study was a nonrandomized trial with the SES, applying the same inclusion and exclusion criteria, endpoints, and protocol definitions. At 5 years, the death/stroke/MI event-free survival rate was 87.1% in the ARTS II SES cohort, versus 86.0% (p = 0.1) and 81.9% (p = 0.007) in the ARTS I CABG and BMS cohorts, respectively. The 5-year major adverse cardiac and cerebrovascular event rate in the ARTS II study (27.5%) was significantly higher than the ARTS I study CABG (21.1%, p = 0.02), and lower than in the ARTS I study BMS (41.5%, p < 0.001). The cumulative incidence of definite stent thrombosis was 3.8%. Thirty-two percent (56 of 176) of MACE at 5 years was related to possible, probable, or definite stent thrombosis.

The COBIS (Coronary Bifurcation Stenting) registry (60) compared the long-term clinical outcomes of 1,033 patients treated with SES and 562 patients treated with PES for coronary bifurcation lesions. Treatment with SES was associated with a lower incidence of MACE (HR: 0.53, p < 0.01) and TLR (HR: 0.55, p = 0.02), but not of cardiac death and cardiac death or MI. After propensity-score matching, patients with SES still had fewer MACE and lower TLR incidence than did patients with PES (HR: 0.52, p = 0.02, and HR: 0.48, p = 0.02, respectively). There was no significant difference in the occurrences of stent thrombosis between the groups (0.7%). In patients with bifurcation lesions, the use of SES resulted in better long-term outcomes than did the use of PES, primarily by decreasing the rate of repeat revascularization.

In a pathology study of 40 stented bifurcation lesions (21 BMS and 19 DES), plaque formation in native coronary bifurcations and neointimal growth after DES implantation was significantly less at the flow divider versus the lateral wall (61). A higher prevalence of late stent thrombosis in DES compared with BMS was associated with greater uncovered struts at flow divider sites, which is likely due to flow disturbances.

Ndrepepa et al. (62) investigated the impact of no-reflow phenomenon by angiography on 5-year mortality among 1,406 patients with STEMI treated by primary PCI. Infarct size measured with single-photon emission computed tomography imaging 7 to 14 days after the acute event was 15.0% of the left ventricle in the no-reflow group versus 8.0% in the reflow group (p < 0.001). There were 59 deaths among patients with no-reflow and 73 deaths among patients with reflow (p < 0.001). The Cox proportional hazards model adjusting for infarct size among other variables identified the no-reflow phenomenon as an independent correlate of 5-year mortality (HR: 1.66, p = 0.004). The no-reflow phenomenon after PCI provides prognostic information that is independent of and beyond that provided by infarct size.

Hochholzer et al. (63) evaluated the impact of demographic and clinical variables versus the cytochrome P450 2C19 (CYP2C19) polymorphism on antiplatelet effects of clopidogrel in 760 patients undergoing elective PCI after loading with 600 mg of clopidogrel. Major independent predictors for an insufficient antiplatelet response to clopidogrel were CYP2C19*2 carrier status (OR: 2.74), together with age (OR: 1.03), diabetes mellitus (OR: 1.75), and body mass index (BMI) (OR: 1.06). Classification and regression trees analyses demonstrated that CYP2C19*2 carrier status followed by diabetes mellitus was the best discriminator between a sufficient and an insufficient antiplatelet response to clopidogrel. A full linear regression model including all these parameters could only explain 11.5% of the antiplatelet response (5.2% by CYP2C19*2 carrier status alone). This study suggests that genotyping alone or in combination with clinical factors explains a very small portion of the antiplatelet response to clopidogrel.

Stabile et al. (64), in a single-center registry, evaluated proximal endovascular occlusion in 1,300 patients undergoing carotid artery stenting. Patients received an independent neurological assessment before the procedure and 1 h, 24 h, and 30 days after the procedure. Procedural success was achieved in 99.7% of patients. The 30-day stroke and death incidence was 1.38% (n = 19) and was greater in symptomatic patients (3.04% vs. 0.82%; p < 0.05). The 30-day stroke and death rate was similar among patients at high and average surgical risk. Operator experience, symptomatic status, and hypertension were found to be independent predictors of adverse events. If the remarkably low event rates in this study are reproduced, it may elevate proximal protection to a leading role in carotid stenting.

The PARADISE (Preventing Amputations Using Drug Eluting Stents) trial (65), a prospective registry of 106 patients (118 limbs), investigated the efficacy and safety of DES (n = 228) to prevent amputations in patients with below-the-knee critical limb ischemia. There were no procedural deaths, and 96% of patients were discharged within 24 h. The 3-year cumulative incidence of amputation was 6 ± 2%, survival was 71 ± 5%, and amputation-free survival was 68 ± 5%. Rutherford category, age, creatinine level, and dialysis (p ≤ 0.001 to 0.04) were predictors of death but not amputation. Target limb revascularization occurred in 15% of patients, and repeat angiography in 35% of patients revealed a binary restenosis in 12%. Limb salvage and survival rates in patients treated with DES exceed those of historic controls. The authors conclude that treating below-the-knee critical limb ischemia with DES is an effective and safe means of preventing major amputation and relieving symptoms.

Takano et al. (66) examined the neointimal characteristics of BMS by optical coherence tomography during the early (<6 months, n = 20) and late phases (≥5 years, n = 21) after implantation. Normal neointima proliferated homogeneously, and lipid-laden intima was not observed in the early phase. In the late phase, lipid-laden intima, intimal disruption, and thrombus frequently were found in comparison with the early phase. The appearance of intraintima neovascularization was more prevalent in the late phase than in the early phase (62% vs. 0%, respectively; p < 0.01) and in segments with lipid-laden intima than in nonlipidic segments (79% vs. 29%, respectively; p = 0.026). These remarkable optical coherence tomography finding suggest that neointima within the BMS often transforms into lipid-laden tissue and may explain some of the late adverse events noted with BMS.

Kubo et al. (67) used virtual histology (VH) intravascular ultrasound (IVUS) to investigate the natural history of coronary lesion morphology by performing baseline and 12-month follow-up studies in 216 nonculprit lesions (plaque burden ≥40%) in 99 patients. Lesions were classified into pathological intimal thickening, thin-capped fibroatheroma (TCFA), thick-capped fibroatheroma (ThCFA), fibrotic plaque, and fibrocalcific plaque. At baseline, 20 lesions were VH TCFAs; during follow-up, 15 (75%) VH TCFAs “healed,” 13 became ThCFAs, 2 became fibrotic plaque, and 5 (25%) VH TCFAs remained unchanged. Compared with VH TCFAs that healed, VH TCFAs that did not were located more proximally and had larger lumen, vessel, and plaque areas but not baseline VH IVUS plaque composition. Conversely, 12 new VH TCFAs developed; 6 were pathological intimal thickenings and 6 were ThCFAs at baseline. In addition, plaque area at minimum lumen sites increased significantly in all but fibrous or fibrocalcific plaque. This longitudinal study suggests novel insights into plaque progression, and by inference imaging of stable and active plaques, that will help guide future imaging and therapeutic trials using such techniques.

Bayturan et al. (68) evaluated 3,437 patients with CAD undergoing serial IVUS examination in 7 clinical trials. Patients who achieved an on-treatment LDL cholesterol level of ≤70 mg/dl (n = 951) were stratified as progressors (n = 200) or nonprogressors^. Despite achieving LDL cholesterol ≤70 mg/dl, >20% of patients continued to progress. Progressors demonstrated higher baseline levels of glucose, triglycerides, and a smaller decrease of apo-B at follow-up. Multivariable analysis revealed that independently associated risk factors of progression included baseline percent atheroma volume, diabetes mellitus, increase in systolic blood pressure, less increase in HDL cholesterol, and a smaller decrease in apo-B levels, but not changes in CRP or LDL cholesterol. This study highlights the importance of residual risk factors, particularly LDL particle concentration, in the progression of atherosclerosis in patients who achieve very low LDL cholesterol levels.

In another IVUS study, Nicholls et al. (69) examined the relationship between IVUS measures and CV outcomes, by defining the relationship between baseline and change in percent atheroma volume (PAV) and total atheroma volume and total with MACE in 4,137 patients and 6 clinical trials. Greater baseline PAV was observed in patients with MI, coronary revascularization, or MACE. Importantly, each standard deviation increase in PAV with associated with a 1.32-fold greater likelihood of experiencing MACE. Thus, this study demonstrated a relationship between the burden and progression of coronary atherosclerosis as defined by IVUS and the occurrence of MACE. The investigators contended that their data support the use of IVUS as a modality to predict beneficial effects of new antiatherosclerotic therapies.

The relationship of a panel of oxidative biomarkers and lipoprotein(a) to CAD risk was determined in the prospective case-control study nested in the EPIC (European Prospective Investigation of Cancer)-Norfolk cohort of 45- to 79-year-old apparently healthy men and women followed up for ∼6 years (70). After adjusting for conventional risk factors, the highest tertiles of oxidized phospholipids on apo-B-100 particles and lipoprotein(a) were associated with a significantly higher risk of CAD events (OR: 1.67 and 1.64, respectively; p < 0.001) compared with the lowest tertiles, which was significantly potentiated (approximately doubled) by the highest tertiles of secretory phospholipase A₂ activity and mass but less so for myeloperoxidase and lipoprotein-associated phospholipase A₂ activity. After taking into account the Framingham Risk Score, c-index values progressively increased when oxidative biomarkers were added to the model. This EPIC-Norfolk study links pathophysiologically related oxidation-specific biomarkers and lipoprotein(a) with CAD events and suggests that they provide cumulative predictive value when added to traditional CV risk factors.

A systematic review of 40 studies involving 58,000 participants measured apo(a) isoforms and determined their risk of vascular disease (71). Thirty-six studies used broadly comparable phenotyping and analytic methods to assess apo(a) isoform size. These studies yielded a combined relative risk for CHD of 2.08 for subjects with smaller versus larger apo(a) isoforms. There was substantial heterogeneity among these studies (I² = 85%, 80% to 89%), which was mainly explained by differences in the laboratory methods and analytic approaches used. In the 6 studies of ischemic stroke that used comparable phenotypic methods, the combined relative risk was 2.14. Thus, persons with smaller apo(a) isoforms have an approximately 2-fold higher risk of CHD or ischemic stroke than do those with larger proteins.

Alcohol septal ablation represents an interventional therapy for hypertrophic cardiomyopathy. Agarwal et al. (72) performed a meta-analysis of 12 studies in an attempt to compare the efficacy of alcohol ablation versus surgical myectomy. No significant difference between alcohol ablation or surgical myectomy could be found in either short-term or long-term mortality or post-interventional functional status, functional class, ventricular arrhythmias, reinterventions, or mitral regurgitation. However, septal alcohol ablation did increase the risk of right bundle branch block, the need for a permanent pacemaker, and was associated with a significantly higher residual gradient in the left ventricular (LV) outflow track. In the absence of a randomized prospective clinical trial comparing these 2 therapeutic approaches, this meta-analysis suggests that septal alcohol ablation yields similar results to those for the treatment of hypertrophic obstructive cardiomyopathy.

Recent studies have cast doubt on the hypothesis that paroxysmal atrial fibrillation (AF) progresses to persistent AF (73). De Vos et al. (73) studied the clinical correlates of patients in whom paroxysmal AF did and did not progress to persistent AF, to define a scoring system for progression. In 1,219 paroxysmal AF participants, AF progressed at 1 year in 15%. On multivariate analysis, HATCH (an acronym for heart failure, age, previous transient ischemic attack or stroke, chronic obstructive pulmonary disease [COPD], and hypertension) independently predicted AF progression. The researchers created a HATCH score for AF progression: half of patients with HATCH score = 5 but only 6% of patients with score = 0 progressed to persistent AF; HATCH thus had prognostic value. An accompanying editorial (74) agreed that the HATCH score may identify patients likely to progress to persistent AF and, if validated, may provide important bedside prognostic information.

Several studies have associated single nucleotide polymorphisms (SNPs) with AF, particularly those on chromosomes 4q25 and 16q22 (75- 76). However, applying these data to clinical management has been unclear. A thought-provoking study in JACC by Husser et al. (77) showed that SNPs on chromosome 4q25 may identify patients with AF recurrence after ablation. In 195 AF patients undergoing ablation for drug, the authors studied SNPs rs2200733 and rs10033464 on chromosome 4q25 and prospectively assessed for AF recurrence per guidelines. Recurrent AF occurred in 37% within 7 days (“early”), and 21% at 3 to 6 months (“late”), and was not predicted by clinical characteristics. However, the presence of any variant allele (of identified SNPs) was strongly associated with early recurrence (OR: 1.994) and late recurrence (OR: 4.182). While calling for additional studies, an accompanying editorial (76) agreed that polymorphisms on chromosome 4q25 may modulate risk for AF recurrence after catheter ablation, pointing to a potential clinical role in risk stratification.

Ablation for persistent AF may involve extensive ablation to isolate the pulmonary veins (PV), ablate the left atrial roof, and interrupt circuits in other locations. However, the mechanistic rationale for each of these lesion sets is unclear. Nishida et al. (78) mapped canine AF circuits, then assessed the impact of the PV isolation and roof ablation of an extensive AF ablation procedure. The PV isolation failed to terminate AF, but did decrease AF vulnerability to single extrastimuli by increasing effective refractory periods. Conversely, left atrial roof ablation terminated AF in 67% of dogs and reduced AF duration without affecting AF vulnerability. The authors conclude that PV isolation and left atrial roof ablations have beneficial but limited actions in this canine model, further emphasizing the need to systematically study individual step-wise components to refine AF ablation procedures.

The search for more effective pharmacological therapy for AF continues. Burashnikov et al. (79) used ex vivo canine perfused canine atrial, PV, and ventricular preparations to study the independent and concomitant effects of ranolazine and dronedarone on AF vulnerability (79). The authors found that low concentrations of ranolazine and dronedarone weakly suppressed AF, yet their combination potently depressed atrial-selective sodium channel activity and suppressed AF. This study supports future clinical trials.

An elegant report by Fedorov et al. (80) used optical mapping of atria from human explanted hearts to define the functional sinoatrial node (SAN). Optical signals from the SAN region showed diastolic depolarization and multiple upstroke components, corresponding to the separate excitations of SAN and atrial layers. Excitation originated in the middle of the SAN, then spread slowly and anisotropically from it, to excite atrial myocardium via superior, middle, and/or inferior sinoatrial pathways. Notably, the oval SAN was functionally insulated from the atrium by connective tissue, fat, and coronary arteries, except for these pathways. The investigators conclude that these are the first data to show the location of the leading SAN pacemaker site, the pattern of excitation within the human SAN, and the conduction pathways into the right atrium. These findings have clinical significance in understanding the pathophysiology of atrial tachyarrhythmias.

A definitive diagnosis for syncope is often difficult to achieve. The ROSE (Risk Stratification of Syncope in the Emergency Department) study, published by Reed et al. (81), prospectively developed a clinical decision rule to predict serious 1-month outcome and all-cause mortality among patients presenting to the emergency department with syncope. From this single-center, prospective, observational study was derived the ROSE rule and subsequently validated it in 550 patients each. Independent predictors of serious 1-month outcome or all-cause death that occurred in 7.3% patients were brain natriuretic peptide (BNP) concentration >300 pg/ml, positive fecal occult blood, hemoglobin <9 g/dl, oxygen saturation <94%, and Q-wave on electrocardiogram; and were similar in the validation cohort. The ROSE rule had a sensitivity and specificity of 87.2% and 65.5%, respectively, and a negative predictive value of 98.5%. Elevated BNP alone was a major predictor of serious CV outcomes (8 of 9 deaths, 89%). Thus, the ROSE rule (and particularly its BNP component) has excellent sensitivity and negative predictive value for identifying high-risk patients with syncope.

The automated external defibrillator (AED) has the potential to reduce mortality from sudden cardiac arrest (SCA) in high-risk public places. Weisfeldt et al. (82) reported the relationship of AED application (before emergency medical services) to survival to hospital discharge in a cohort with nontraumatic out-of-hospital SCA. From the Resuscitation Outcome Consortium, 4,403 out-of-hospital received bystander cardiopulmonary resuscitations (CPRs) without AED use, and 289 CPRs with AED were applied by health care workers (32%), lay volunteers (35%), police (26%), or others (7%). Survival was 9% (382 of 4,403) with bystander CPR without AED, 24% (69 of 289) with AED use, and 38% (64 of 170) with AED shock delivered. In multivariate analyses, AED use was associated with greater likelihood of survival (OR: 1.75; p < 0.002). Extrapolating the observed survival benefit from to the entire U.S. and Canadian population (330 million), AED application by bystanders might save 474 lives a year.

Kanoupakis et al. (83) tested the hypothesis that serum markers of collagen turnover, reflecting turnover in ventricular myocardium, may contribute to substrates for ventricular arrhythmias. In 70 patients with nonischemic cardiomyopathy, and an implantable cardioverter-defibrillator (ICD) for primary prevention, the authors measured serum C-terminal propeptide of collagen type-I, C-terminal telopeptide of collagen type-I, matrix metalloproteinase (MMP)-1, and tissue inhibitor of MMP-1. The authors found appropriate ICD therapies in 14 of 70 patients during 1-year follow-up. Pre-implantation serum levels of C-terminal telopeptide of collagen type-I were significantly baseline MMP-1 and tissue inhibitor of MMP-1 higher in patients with ICD therapy than without ICD therapy. The authors concluded that serum markers of collagen turnover, possibly reflecting altered extracellular matrix that influences the arrhythmogenic substrate in nonischemic cardiomyopathy, may predict arrhythmic events in ICD recipients.

Data continue to accrue on ICD risks. Lee et al. (84) reported complications from ICD insertion in a multicenter registry of 18 centers. The authors noted 45-day major complications in 4.1% of procedures. Implantation of a cardiac resynchronization defibrillator or dual-chamber device was associated with an increased risk of major complications, which were higher in women and when end-systolic dimension exceeded 45 mm. Major complications (excluding death) early after ICD insertion were associated with increased risk of death. Direct ICD-related complications were associated with higher risk for early death (HR: 24.89), whereas indirect complications increased the risk for near-term death (HR: 12.35). The authors concluded that major complications occurred in 4.1% of de novo ICD inserts, were strongly associated with device type, and were associated with increased risk of mortality.

Chung et al. (85) reported on compliance with, and efficacy of, the wearable cardioverter-defibrillator (WCD) for prevention of sudden death in patients whose risk for ventricular arrhythmias is being ascertained, or who temporarily cannot receive an ICD because of infection or other comorbidity. In 6,569 WCD recipients, daily use was >90% of the day in 52% of patients, with <15% of patients discontinuing use because of discomfort or adverse reactions. Eighty sustained ventricular tachycardia/ventricular fibrillation (VT/VF) events were noted in 59 patients (1.7%). First-shock success was 100% for unconscious VT/VF and 99% for all events, and resulted in a 89.5% survival from VT/VF events. During WCD use, 3,541 of 3,569 patients (99.2%) survived overall. Using the Social Security Death Index, long-term mortality was not significantly different from first ICD implant patients. As editorialized by Verdino (86), wear time with the WCD was satisfactory and the WCD provided a survival from sudden death comparable to that with ICD, although asystole was not addressed by the WCD.

Nakahara et al. (87) report a mapping study for substrates for VT, in cardiomyopathy patients with a particular focus on low voltage late potentials (LP) as targets for catheter ablation. In 33 cardiomyopathy patients referred for VT ablation, they mapped the endocardium (n = 33) and epicardium (n = 19) to identify LP, defined as electrograms <1.5 mV with onset after the QRS interval, and very late potentials (vLP), defined as onset >100 ms after the QRS. Sampling 564 ± 449 endocardial points and 726 ± 483 epicardial points in the left ventricle per patient, the authors found low voltage areas in the endocardium and epicardium. Patients with ischemic myopathy had a larger endocardial low voltage area and frequencies of vLP than nonischemic myopathy (NICM) patients. Notably, LP-targeted ablation was effective in ischemic myopathy patients (82% nonrecurrence at 12 months) but less in NICM patients (50% at 15 months). The authors concluded that the cause of signal types often targeted for VT ablation (LP and vLP) may differ between ischemic myopathy and NICM, and that approaches other than LP ablation, and pace-mapping may be required in NICM patients.

As suggested by the above study, epicardial mapping is increasingly used during VT ablation. Sacher et al. (88) examined the necessity and safety for this approach from VT ablation at 3 referral centers. Of 913 VT ablations, 156 procedures (17%) involved epicardial mapping and/or ablation, performed in 134 patients mostly after a previous VT ablation. Notably, 51 patients had ischemic cardiomyopathy, 39 had nonischemic cardiomyopathy, 14 had arrhythmogenic right ventricular cardiomyopathy, and 30 had other types of cardiomyopathy. Overall, 136 procedures were performed by percutaneous subxiphoid puncture, 14 by a surgical subxiphoid approach, and 6 during open-heart surgery. Epicardial ablation was performed in 121 of 156 procedures (78%) and was subsequently delivered endocardially in 21%. Twenty patients subsequently required repeat procedures, and the epicardium could be reaccessed in all but 1 patient. The authors observed a total of 8 (5%) major complications acutely, including 7 epicardial bleeding events and 1 coronary stenosis. After 23 ± 21 months of follow-up, 3 delayed complications included 1 major pericardial inflammatory reaction, 1 delayed tamponade, and 1 coronary occlusion after 2 weeks. Constrictive pericarditis or phrenic nerve injuries were not observed. An accompanying editorial (89) places these data in the context of prior studies, in which epicardial ablation was also more likely to be required in patients with nonischemic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy, and outlines future trends in VT ablation.

Several studies addressed the link between the LQTS and life-threatening ventricular arrhythmias. Viskin et al. (90) examined the utility of a simple bedside test to improve diagnosis: that is whether short-lived sinus tachycardia from the orthostatic response to standing exposes abnormal QT prolongation in patients with LQTS. The authors examined 68 patients with LQTS and 82 control subjects. In response to brisk standing, patients and control subjects responded with similar heart rate acceleration of 28 ± 10 beats/min (p = NS). However, the QT interval shortened in controls by 21 ms and lengthened in LQTS patients by 4 ms (p < 0.001), so that corrected QT interval increased by 50 ± 30 ms in controls and 89 ± 47 ms in LQTS patients (p < 0.001). The authors concluded that evaluating the QT-interval response to the brisk tachycardia induced by standing may aid in the diagnosis of LQTS.

Although syncope is highly predictive for future fatal arrhythmias in LQTS, few data exist to stratify such risk. Jons et al. (91) studied 1,059 LQTS patients from the International LQT registry with corrected QT interval >450 ms and syncope as a first symptom. The investigators found that the lowest risk for a “severe arrhythmic event” occurred with only 1 syncopal episode before beta-blocker therapy. In contrast, patients with syncope after starting beta-blocker therapy had a 3.6-fold increase in the risk of severe arrhythmic events compared to patients not treated with beta-blockers. The risk of syncope during beta-blocker therapy was high during childhood in both sexes but higher in women (HR: 2.3, p < 0.001). The authors concluded that patients with LQTS and syncope during beta-blocker therapy are at high risk of life-threatening events, and should be considered for ICDs.

There is increasing evidence that patient-tailored lead location may improve the hemodynamics of CRT (92). Spragg et al. (93) studied the impact of endocardial LV pacing site on the mechanical response to CRT in patients with ICM. The authors studied peak rate of LV pressure increase (dP/dt_max) at baseline, during VDD pacing at the right ventricular apex, and during biventricular pacing from the right ventricular apex and 51 LV endocardial sites in 11 patients with ICM. They used electroanatomic mapping to create color-coded maps of dP/dt_max within the ventricle. The authors found that endocardial biventricular pacing improved dP/dt_max over right ventricular apical pacing. In 7 patients with preexisting CRT leads, LV dP/dt_max was equivalent for endocardial and epicardial pacing, but dP/dt_max at the best endocardial site was higher than achieved with the pre-implanted CRT. An average of 2 optimal endocardial sites (yielding >85% of maximum dP/dt_max) were identified for each patient, located at the extreme basal lateral wall (8 of 11 patients) and elsewhere (9 of 11 patients). Standard mid-LV free wall pacing yielded suboptimal LV function in 73% of patients. Optimal pacing sites were typically located in LV territories remote from the infarct zone. An accompanying editorial emphasized that CRT delivered at the best LV endocardial sites for any given patient was more effective than by pre-implanted coronary sinus leads, confirming results of a paper published in the Journal in 2010 regarding patients with nonischemic cardiomyopathy, by Derval and Jais (94).

Multiple configurations of ventricular tachycardias are typically inducible in patients in whom ICDs have been implanted. Yoshida et al. (95) set out to determine whether an electrogram recorded on the ICD could in fact differentiate the actual clinical arrhythmias occurring from others inducible at the time of testing (95). They found that electrograms stored on the ICD accurately identified clinical VTs from 98% of other VTs. By visual inspection of the ICD electrograms, 96% of clinical VTs were accurately differentiated from previously undocumented VTs. In addition, pace mapping based on ICD electrograms were found to be useful for identifying a VT exit site. This study validates the usefulness of defibrillator electrograms for recognizing clinical VTs. In an accompanying editorial, Almendral and Marchlinski (96) indicate that this work suggests that in the management of VT with catheterization ablation procedures, ICD electrograms could become the new “standard” link between spontaneous phenomena and induced arrhythmias.

Singh et al. (97) reviewed the clinical trials reported to date on the new antiarrhythmic drug developed for the treatment of AF. The authors summarized the DAFNE (Dronedarone Atrial Fibrillation Study after Electrical Cardioversion), EURIDIS (European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm), ADONIS (American-Australian-African Trial with Dronedarone in Patients with Atrial Fibrillation or Atrial Flutter for the Maintenance of Sinus Rhythm), and ATHENA (A Trial with Dronedarone to Prevent Hospitalization or Death in Patients with Atrial Fibrillation) trials and noted a modest antiarrhythmic drug efficacy of dronedarone compared with other antiarrhythmic drugs and placebo. Patients administered dronedarone had a recurrence rate of AF or atrial flutter of 43% compared with 54% in patients on placebo (p < 0.0001), comparable to quinidine. In the DIONYSIS (Efficacy and Safety of Dronedarone versus Amiodarone for the Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation) study, the composite endpoint of AF recurrence or premature drug discontinuation in patients on drug for at least 6 months was reached by 74% of patients on dronedarone versus 55% on amiodarone. Dronedarone was effective in reducing ventricular rate on AF compared with placebo. Dronedarone was found to increase mortality in the ANDROMEDA (European Trial of Dronedarone in Moderate to Severe Congestive Heart Failure) trial, in patients with moderate to severe CHF. This increased mortality rate appeared to be due largely to worsening of heart failure, predominately in those patients with recently decompensated heart failure. In contrast, in the ATHENA trial, in patients with compensated heart failure, there was a 24% reduction in combined risk of CV hospitalization and all-cause mortality compared with placebo at 21 months follow-up. The Food and Drug Administration approved dronedarone for treatment of AF/atrial flutter largely on the basis of the results of the ATHENA trial. The researchers note, however, that in a pooled analysis of these 6 studies, in a total of 6,771 patients, dronedarone treatment was not significantly different with respect to placebo in the incidence of all-cause mortality of CV hospitalization. With respect to side effects, dronedarone was noted in these studies to cause a slight increase in creatinine due to inhibition of renal tubular secretion. The main clinical side effects were diarrhea, nausea, and vomiting. Thus, the authors concluded that dronedarone was moderately effective in the treatment of AF/atrial flutter, it may reduce CV hospitalization and all-cause mortality, it had less toxicity than amiodarone, it should not be used in patients with decompensated heart failure, and it is most likely a second- or third-line agent. The researchers also noted that its high cost (as much as $9 per day) makes it uncertain if it will be cost effective compared with generic amiodarone.

Fein et al. (98), provide an important perspective on the use of CRT outside of the guidelines from the National Cardiovascular Data Registry (NCDR) ICD registry. More than 75% of hospitals nationally submit data to this registry. The authors examined a cohort of 45,392 CRT-defibrillator implants for primary prevention of sudden death. They defined “off-label” implants, however, as those in patients with an ejection fraction (EF) >35%, New York Heart Association (NYHA) functional class <III, or a QRS duration <120 ms. The investigators found that 23.7% of devices were implanted without meeting all 3 implant criteria, most often due to NYHA functional class <III or QRS duration <120 ms. Physician training and insurance payer were weakly associated with the likelihood of off-label use. Thus, nearly 25% of patients undergoing CRT therapy reported to the NCDR registry during the study time frame did not meet guideline-based indications for device implantation. While the investigators refrain from equating off-label use of CRT devices with inappropriate care, they do suggest that these apparently aberrant practices require careful scrutiny.

The effects of chronic stretch due to mitral valve stenosis and its reversal after mitral commissurotomy (MC) on the electrophysiological properties of the human atria were reported this year (99). Because atrial stretch due to mitral stenosis is a known common cause of AF, studying the atrial electrophysiology before and after the relief of this stretch would appear to be good method to correlate electrophysiologic characteristics with a substrate known to predispose to AF. The researchers evaluated 21 patients with mitral stenosis undergoing MC, before and after intervention. They observed that, immediately after MC, there was significant increase in mitral valve area, with significant decrease in left atrial and pulmonary artery pressures and left atrial volume. That was associated with reduction in P-wave duration, an increase in conduction velocity and voltage in both the left atrium and right atrium, but no change in effective refractory period (ERP). Late after MC, mitral valve area remained improved, but there was an even further decrease in P-wave duration, associated with further increases in conduction velocity and voltage in the right atrium, and ERP decreased. They concluded that the atrial electrophysiologic and electroanatomic abnormalities that result from chronic stretch due to mitral stenosis do significantly reverse after MC, and that the substrate predisposing to atrial arrhythmias may therefore be reversed as well. The authors did not assess inducibility of AF or report on the incidence of AF late after MC. These observations suggest that abnormalities in conduction velocity and voltage may be more important in generating the substrate predisposing to AF than shortening of ERP, which, interestingly, was observed to shorten even further late after MC in these patients.

Tedrow et al. (100) evaluated the effects of BMI on the risk of new AF during nearly 13 years of follow-up in the Women's Health Study, to assess the relationship between changes in BMI and incident AF. They note that both obesity and AF are increasing public health problems, but the role of obesity in AF is uncertain. Over 12.9 ± 1.9 years of follow-up, 834 AF events were confirmed after chart review. The researchers determined that BMI was linearly associated with AF risk, with a 4.7% (p < 0.0001) increase in risk with each kg/m². When long-term measures of BMI were utilized to estimate dynamic risk, overweight (HR: 1.22, 95% CI: 1.02 to 1.45, p = 0.03) and obesity (HR: 1.65, 95% CI: 1.36 to 2.00, p < 0.0001) were associated with adjusted short-term elevations in AF risk. Participants becoming obese during the first 60 months had a 41% adjusted increase in risk of developing AF (p = 0.02) compared with those maintaining BMI <30 kg/m². The correlation between BMI and AF risk appeared strongest in women 60 years of age and younger, whereas this correlation was not observed in women older than 60 years at baseline. From their observations, the authors concluded that in this population of initially healthy, middle-aged, female healthcare professionals, elevated BMI was associated with both short- and long-term elevations in AF risk, accounting for a large proportion of incident AF independent of traditional risk factors.