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HIGHLIGHTS FROM JACC

Highlights of the Year in JACC 2009

Anthony N. DeMaria, MD^_*,_*, Jeroen J. Bax, MD, PhD, Ori Ben-Yehuda, MD^_*, Gregory K. Feld, MD^_*, Barry H. Greenberg, MD^_*, Jennifer Hall, PhD, Mark Hlatky, MD, Wilbur Y.W. Lew, MD^||, João A.C. Lima, MD^¶, Alan S. Maisel, MD^||, Sanjiv M. Narayan, MD, PhD^||, Steven Nissen, MD^#, David J. Sahn, MD^_** and Sotirios Tsimikas, MD^_*

^_* Cardiology Division, UCSD Medical Center, San Diego, California
Leiden University Medical Center, Leiden, the Netherlands
University of Minnesota, Minneapolis, Minnesota
Stanford University, Stanford, California
^|| Veterans Affairs Medical Center, San Diego, California
^¶ Johns Hopkins Hospital, Baltimore, Maryland
^# Department of Cardiology, Cleveland, Clinic, Cleveland, Ohio
^_** Pediatric Cardiology, Oregon Health and Science University, Portland, Oregon

^_* Reprint requests and correspondence: Dr. Anthony N. DeMaria, Cardiology Division, UCSD Medical Center, 200 West Arbor Drive, San Diego, California 92103-8411

Key Words: general cardiology • interventional cardiology • cardiac imaging • heart failure • heart rhythm disorders • valvular heart disease • congenital heart disease

	Interventional Cardiology

Top Interventional Cardiology Heart Failure Electrophysiology Echocardiography CT and Nuclear Imaging MRI Valvular Heart Disease Pre-Clinical Research Biomarkers Genomics/Genetics Congenital Heart Disease JACC White Papers References

 
Long-term outcomes.   A patient-level, pooled analysis of 4 randomized sirolimus-eluting stent (SES) trials (1) in 1,748 patients assigned to receive either an SES or bare-metal stent (BMS) showed a continued benefit of SES on target vessel revascularization (TVR) (15.2% vs. 30.1%; p < 0.0001) without differences in 5-year rate of death, myocardial infarction (MI), the composite of death/MI, or stent thrombosis (ST). The annualized rates of definite/probable ST after 1 year were 0.4% for SES and 0.2% for BMS. SES compared with BMS demonstrated superior 5-year reduction of TVR without an increase in rates of death, MI, or ST.

DES in ST-segment elevation myocardial infarction (STEMI).   A meta-analysis identified 13 randomized trials (n = 7,352) comparing BMS versus DES in STEMI (2). Over a 2-year follow-up, DES significantly reduced TVR (relative risk [RR]: 0.44), without increasing MI or ST. Similarly, in 18 registry studies (n = 26,521), DES significantly reduced TVR (RR: 0.54; 95% confidence interval) without an increase in MI. Death was significantly lower with DES within 1 year of the index percutaneous coronary intervention (PCI), but there were no differences within 2 years. The use of DES appears safe and efficacious in patients with STEMI.

DES in saphenous vein grafts (SVGs).   Eighty patients with 112 lesions in 88 SVGs were randomized to a BMS or paclitaxel-eluting stent (PES) (3). Binary angiographic restenosis occurred in 51% of the BMS-treated lesions versus 9% of the PES-treated lesions. During a median follow-up of 1.5 years, the PES patients had less target lesion revascularization (TLR) (28% vs. 5%) and target vessel failure (46% vs. 22%), and a trend toward less TVR (31% vs. 15%). In SVG lesions, PES are associated with lower rates of angiographic restenosis and target vessel failure than BMS.

Coronary artery disease.   A total of 130 patients with significant proximal left anterior descending coronary artery (LAD) coronary artery disease were randomized to either SES (n = 65) or minimally invasive direct coronary artery bypass (MIDCAB) surgery (n = 65) (4). Major adverse cardiac events (MACE) at 12 months occurred in 7.7% of SES patients versus 7.7% after MIDCAB (p = 0.03 for noninferiority). Although noninferiority was observed in death and MI, noninferiority was not established for the difference in TVR (6.2% vs. 0%, noninferiority p = 0.21). Clinical symptoms improved significantly in both treatment groups. In isolated proximal LAD disease, SES is noninferior to MIDCAB surgery at 12-month follow-up with respect to MACE at a similar relief in clinical symptoms.

Coronary vasoconstriction.   Coronary endothelial dysfunction was evaluated in a randomized fashion at 6 months following LAD implantation of zotarolimus-eluting stent (ZES) (n = 20), SES (n = 20), and BMS (n = 10) (5). Incremental intracoronary acetylcholine (Ach) and nitrate infusions were given and coronary diameter evaluated in the 5-mm segments proximal and distal to the stent. In the DES groups, more intense vasoconstriction was observed at 6-month follow-up than before stenting. Endothelial function associated with BMS was most preserved, whereas responses to ZES were more preserved compared with SES. This study suggests that long-term vasomotor responses differ by stent type, and this may have clinical implications in explaining recurrent symptoms in some patients following DES.

Rescue PCI.   The long-term outcomes of rescue PCI was reported in the REACT (Rescue Angioplasty Versus Conservative Treatment or Repeat Thrombolysis) trial, which had shown a significant 6-month benefit favoring rescue PCI following failed thrombolytic therapy (6). One-year event-free survival for patients randomized to rescue PCI was 81.5%, compared with 64.1% for repeat thrombolysis and 67.5% for conservative therapy (p = 0.004). Adjusted hazard ratio (HR) for a median of 4.4 years for overall mortality for rescue PCI was 0.41 versus repeat thrombolysis and 0.43 for rescue PCI versus conservative therapy. An accompanying meta-analysis (7) of 6 trials addressing this issue pooling 908 patients showed a nonsignificant reduction in mortality (odds ratio [OR]: 0.74), although underpowered. The authors suggested rescue PCI is the best option for failed thrombolysis.

Statins in PCI.   In another study targeted toward assessing the efficacy of acute statin therapy prior to PCI, Di Sciascio et al. (8) implemented a reloading of atorvastatin just prior to intervention. They randomized 383 patients to either an atorvastatin reload (80 mg 12 h before intervention, with a further 40 mg immediately pre-procedure), or placebo. All patients had been on statin therapy prior to the intervention. The primary end point (30-day incidence of MACE) occurred in 3.7% of patients who received the atorvastatin reload and 9.4% in the placebo arm (p = 0.03), driven primarily by reduction in periprocedural myocardial infarction. Multivariant analysis showed that atorvastatin reload was a predictor of 30-day adverse events (OR: 0.50). In an accompanying editorial, Ellis and Anwaruddin (9) comment that based upon a large body of evidence, including the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) study, it seems indisputable that pre-treatment with statins benefits patients undergoing PCI, likely due to a pleiotropic effect of the agents.

In the NAPLES II (Novel Approaches for Preventing or Limiting Events II) trial, (10) atorvastatin (80 mg, n = 338) versus no statin treatment (control group; n = 330) was administered the day before elective PCI in 668 statin-naive patients. The incidence of a periprocedural MI was 9.5% in the atorvastatin group and 15.8% in the control group. This study expands the acute efficacy of high-dose statins to the periprocedural period and suggests a viable modality to further reduce the incidence of periprocedural MI in elective PCI.

Registry studies.   Six large registry studies were published evaluating clinical outcomes in patients treated with DES (11). The Western Denmark Heart Registry demonstrated in 2,395 consecutive patients followed up for 2 years that the incidence of definite ST was 0.64% in BMS, 0.50% in SES, and 1.30% in PES patients. The incidence of MI was 3.8%, 4.1%, and 5.3% in BMS-, SES-, and PES-treated patients. Patients treated with PES had an increased risk of ST in the 2-year follow-up period and mortality in the second year compared with those treated with BMS and SES. The Dutch Stent Thrombosis Registry (12) documented in 21,009 patients treated with either a BMS or DES that 437 patients (2.1%) presented with a definite ST. A total of 140 STs were acute, 180 were subacute, 58 were late, and 59 were very late. Important correlates of ST were discontinuation of clopidogrel, undersizing of the coronary stent, present malignancy, and intermediate (50% to <70%) coronary stenosis proximal to the culprit lesion. In the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) (13), 35,478 DES were implanted at 22,962 procedures in 19,004 patients, and 1,807 restenoses were reported over a mean 29 months follow-up. In diabetic patients, the adjusted risk of restenosis was higher, and restenosis was twice as frequent with the ZES than with other DES. Restenosis rate with PES was unrelated to diabetes. Mortality did not differ between different DES.

Ko et al. (14) using propensity score matching analysis in 6,944 off-label and 9,126 on-label PCI patients demonstrated that for patients with off-label indications, rates of TVR at 3 years were significantly lower with DES compared with BMS (11.6% vs. 15.3%, p < 0.001). Mortality rates were significantly lower among off-label patients treated with DES compared with BMS at 3 years of follow-up (6.9% vs. 10.5%, p < 0.001). For patients with on-label indications, the use of DES was associated with significantly lower rates of TVR, but composite rates of MI or death were not significantly different from BMS. Data from the SCAAR registry (15) with a minimum follow-up of 1 year and a maximum of 4 years showed no significant differences between on-label DES and BMS (adjusted HR: 1.02) or between off-label DES and BMS (adjusted HR: 0.95) use with regard to the incidence of MI and death. Off-label use of DES did not lead to significant differences in the combined risk of death and MI compared with BMS throughout the whole spectrum of clinical indications.

Finally, the X-SEARCH (Xience V Stent Evaluated at Rotterdam Cardiac Hospital) Registry (16) evaluated 649 consecutive unselected patients treated with everolimus-eluting stents (EES) and 6-month clinical end points were compared with 3 historical cohorts. The EES group demonstrated a higher incidence of all-cause mortality than the SES group and a lower incidence of TVR than the BMS group. Multivariate adjustment demonstrated that BMS was associated with higher TVR and MACE risk than EES (adjusted HR for TVR: 2.02; adjusted HR for MACE: 2.15) that SES had a clinical outcome similar to that of EES, and that PES had a higher risk of MACE than did EES.

Due to the difficultly adjusting for confounding variables, registry studies should be considered hypothesis generating in lieu of randomized controlled trials.

Antiplatelet and antithrombotic therapy.   In the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, 3,602 patients with STEMI undergoing primary PCI were randomized to bivalirudin or unfractionated heparin plus a glycoprotein (GP) IIb/IIIa inhibitor (17). Randomization was stratified by thienopyridine loading dose, which was determined before random assignment. Patients in the 600-mg (n = 2,158) compared with the 300-mg (n = 1,153) clopidogrel loading dose group had significantly lower 30-day unadjusted rates of mortality (1.9% vs. 3.1%, p = 0.03), reinfarction (1.3% vs. 2.3%, p = 0.02), and definite or probable ST (1.7% vs. 2.8%, p = 0.04), without higher bleeding rates. Compared with unfractionated heparin plus a GP IIb/IIIa inhibitor, bivalirudin monotherapy resulted in similar reductions in net adverse cardiac event rates within the 300- and 600-mg clopidogrel loading dose subgroups (p interaction = 0.41). By multivariable analysis, a 600-mg clopidogrel loading dose was an independent predictor of lower rates of 30-day MACE (HR: 0.72, p = 0.04).

A substudy of the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial (18) evaluated the relative impact of spontaneously occurring and periprocedural MI on survival 1 year after PCI in 7,773 non-STEMI patients. Periprocedural MI developed in 466 patients, and spontaneous MI developed in 200 patients. Patients developing spontaneous and periprocedural MI compared with those patients without MI had significantly greater unadjusted rates of mortality at 30 days and at 1 year. In a time-updated multivariable analysis, spontaneous MI was a powerful independent predictor of subsequent mortality (HR: 7.49, p < 0.0001), whereas periprocedural MI was not a significant predictor of mortality (HR: 1.30). This study demonstrates that spontaneous MI unrelated to PCI is a powerful predictor of subsequent mortality. In contrast, periprocedural MI is not an independent predictor of mortality, but reflects baseline risk, atherosclerosis burden, and procedural complexity.

Unprotected left main coronary artery (LMCA) interventions.   The ISAR-LEFT-MAIN (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for Unprotected Coronary Left Main Lesions) trial (19) randomized 607 patients with symptomatic coronary artery disease undergoing PCI for unprotected LMCA to PES or SES. At 1 year, the cumulative incidence of death, MI, or TLR was 13.6% in the PES and 15.8% in the SES group without a difference in definite ST (p = 0.57). Mortality at 2 years was 10.7% in the PES and 8.7% in the SES group. Angiographic restenosis was 16.0% with PES and 19.4% with SES (p = 0.30). Implantation of either PES or SES in unprotected LMCA lesions is safe and effective, and both of these DES provide comparable clinical and angiographic outcomes.

In the LE MANS (Left Main Coronary Artery Stenting) (20) multicenter prospective registry of 252 patients undergoing unprotected LMCA, DES were implanted in 36.2% of patients. Major adverse cardiovascular and cerebral events (MACCE) occurred in 4.8% patients during the 30-day period, which included 4 (1.5%) deaths. After 12 months, there were 17 (12.1%) angiographically confirmed cases of restenosis. During long-term follow-up (mean 3.8 years) there were 64 (25.4%) MACCE and 35 (13.9%) deaths. The 5- and 10-year survival rates were 78.1% and 68.9%, respectively. The DES lowered both mortality and MACCE for distal unprotected LMCA lesions when compared with BMS.

The multicenter, retrospective FAILS (Failure in Left Main Study) registry of DES restenosis (21) in unprotected LMCA stenting showed that restenosis occurred in 70 of 718 patients (9.7%). Of these, 59 were treated percutaneously, whereas 7 patients underwent bypass surgery and 4 were treated medically. In-hospital MACE included no periprocedural MI and only 1 death. Patients treated with medical, interventional, and surgical therapy had the following MACE rates, respectively: 50%, 25.4%, and 14.3%. Definite, probable, and possible ST occurred in 0 (0%), 1 (1.4%), and 1 (1.4%) patient, respectively. This study suggested that DES restenosis in LMCA can be managed with a minimally invasive approach, achieving favorable early and late results.

The MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) (22) Registry followed 858 consecutive patients with unprotected LMCA stenosis treated with SES (n = 669) or PES (n = 189) for 3 years. The adjusted risk of death, MI, and TVR was similar among SES and PES. The 2 groups also showed a comparable adjusted rate of each component of outcome: death (9.1% vs. 11.0%), MI (8.1% vs. 8.0%,), and TVR (12.1% vs. 10.6%). The 3-year rates of definite or probable ST were 0.6% in the SES group and 1.6% in the PES group.

In view of the above and other recent studies in the literature, viewpoints have been proposed by several groups to consider a revision of the guidelines for unprotected LMCA interventions (23,24). In particular, a JACC White Paper by Kandzari et al. (25) on behalf of the American College of Cardiology (ACC) Interventional Scientific Council reviewed the current evidence on unprotected LMCA PCI, and emphasized improvements in PCI techniques in parallel with the benefits of DES to reduce clinical restenosis. Clearly stating that ACC/American Heart Association (AHA) guidelines do not currently endorse PCI for unprotected LMCA disease, they proposed future directions and investigations to evaluate catheterization-based treatment strategies as possible therapeutic options to bypass surgery.

Percutaneous valve.   State-of-the art reviews by Piazza et al. (26) on transcatheter mitral and pulmonary valve therapy and Zajarias and Cribier (27) on percutaneous aortic valve replacement brought the readers to the cutting edge of this rapidly evolving field.

Stent fracture.   Nakazawa et al. (28) performed a pathologic assessment on stent fracture using high-contrast film-based radiographs of 177 consecutive lesions from the CVPath DES autopsy registry. Stent fracture was documented in 51 lesions. Sixty-seven percent of fracture lesions with a transection causing a gap in stent segment were associated with adverse pathologic findings at fracture sites. Longer stent length, use of SES, and longer duration of implant were identified as independent risk factors of stent fracture by logistic regression analysis.

Renal artery stenosis (RAS).   Leesar et al. (29) investigated the comparative accuracy of renal translesional pressure gradients, intravascular ultrasound, and angiographic parameters in predicting hypertension improvement after stenting of RAS in 62 patients. A hyperemic systolic gradient 21 mm Hg provided the highest accuracy in predicting hypertension improvement after stenting of RAS.

Niacin and carotid atherosclerosis.   Lee et al. (30) evaluated the effects of nicotinic acid (NA) on progression of atherosclerosis and measures of vascular function in a double-blind, randomized, placebo-controlled study of 2-g daily modified-release NA added to statin therapy in 71 patients with low high-density lipoprotein cholesterol (HDL-C) (<40 mg/dl) and either: 1) type 2 diabetes with coronary heart disease (CHD); or 2) carotid/peripheral atherosclerosis. The primary end point was the change in carotid artery wall area, quantified by magnetic resonance imaging (MRI), after 1 year. NA increased HDL-C by 23% and decreased low-density lipoprotein cholesterol by 19%. At 12 months, NA significantly reduced carotid wall area compared with placebo (adjusted treatment difference: –1.64 mm² [95% confidence interval: –3.12 to –0.16]; p = 0.03). In statin-treated patients with low HDL-C, high-dose modified-release NA, compared with placebo, significantly reduces carotid atherosclerosis within 12 months.

To further define the effectiveness of drug-eluting stents versus bare metal stents in real-world clinical practice, Douglas et al. (31) examined the National Cardiovascular Data Registry (NCDR) for the results of percutaneous intervention in their patients. They assembled data on an extraordinary number of variables in 262,700 patients from 652 NCDR sites and were able to assess outcomes including death, MI, revascularization, major bleeding, and stroke. DES, implanted in 217,675 patients, had lower unadjusted rates of death (12.9% vs. 17.9%), MI (7.3% vs. 10.0% of 100 patients), and revascularization (23.0% vs. 24.5% of 100 patients) than BMS implanted in 45,025. The benefit of DES was observed in all subgroups and persisted throughout a 30-month follow-up. These data clearly support the efficacy and safety of DES in Medicare-age patients.

Acute coronary syndromes.   Antithrombotic and antiplatelet treatments, particularly in the setting of acute coronary syndromes (ACS), continue to be areas of intense research. Although fondaparinux in comparison to enoxaparin reduced major bleeding while preserving anti-ischemic efficacy in the OASIS-5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) study, whether this advantage extended to treatment with concomitant GP IIb/IIIa inhibitors or thienopyridines was unclear. In a subgroup analysis by Jolly et al. (32), there was a 40% reduction in major bleeding with fondaparinux versus enoxaparin in the GP IIb/IIIa subgroup, as well as in those receiving thienopyridines, with similar rates of ischemic events. The authors conclude that the benefit of fondaparinux over enoxaparin extends to patients receiving both thienopyridines and GP IIb/IIIa antagonists. The results are particularly interesting, as in the ACUITY trial of bivalirudin, that the reduced bleeding seen with bivalirudin versus heparin did not extend to the combination therapy with GP IIb/IIIa antagonists.

Similarly, Gurbel et al. (33) in the CLEAR PLATELETS-2 (Clopidogrel with Eptifibatide to Arrest the Reactivity of Platelets) study, assessed the added effect of the GP IIb/IIIa inhibitor eptifibatide when added to bivalirudin, both in the presence and absence of clopidogrel pretreatment in 200 patients undergoing elective stenting. Both turbidometric aggregometry and thrombin-induced platelet fibrin clot strength (TIP-FCS) measured by thrombelastography were assessed. Platelet reactivity was significantly reduced by the addition of eptifibatide. Those patients who had a periprocedural MI had evidence of higher platelet reactivity.

The importance of bleeding in invasive cardiology has received increasing attention in recent years. In an analysis of the ACUITY trial, Nikolsky et al. (34) assessed the incidence and implications of gastrointestinal bleeding in the setting of ACS. They found an incidence of 1.3%, with age, baseline anemia, longer duration of antithrombotic and antiplatelet agents treatment prior to angiography, diabetes, smoking, and greater ST-segment deviations as predictors of gastrointestinal bleeding. On multivariate analysis, gastrointestinal bleeding was associated with mortality and ischemic complications, as well as ST. The importance of preventing gastrointestinal complications of antiplatelet agents has led to the frequent prescription of proton pump inhibitors in conjunction with aspirin and clopidogrel. The OCLA (Omeprazole CLopidogrel Aspirin) study (35) highlighted the interaction of omeprazole and clopidogrel. Whether other proton pump inhibitors have a similar effect was investigated by Cuisset et al. in the PACA (Proton Pump Inhibitors and Clopidogrel Association) study (36). They randomized 104 patients undergoing stenting for acute coronary syndromes to omeprazole versus pantoprazole in addition to aspirin and clopidogrel. After a month of treatment, platelet responsiveness to clopidogrel was superior in the group given pantoprazole with fewer nonresponders (44% vs. 23%; p = 0.04), suggesting the preferential use of pantoprazole in the setting of clopidogrel therapy.

The complexity of clopidogrel's metabolism was further emphasized in an analysis of the CLARITY–TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28) trial (37). Building on an initial report in the Journal in 2008 from Bliden et al. (38), which showed an association of cigarette smoking, a known inducer of the cytochrome p450 system, with enhanced response to clopidogrel, the authors examined the interaction of clopidogrel and smoking in 3,429 STEMI patients and its impact on clinical outcomes. They found that smokers (at least 10 cigarettes a day) had a particularly enhanced benefit from clopidogrel (adjusted OR for a closed infarct-related artery or death/MI before angiography of 0.49 compared with 0.72). The findings should, of course, not be seen as an endorsement of smoking but rather as further highlighting the importance of clopidogrel activation by the cytochrome system.

Clopidogrel initiation prior to early invasive management is recommended by the ACC/AHA guidelines for ACS patients, but is often withheld due to concerns that bleeding may occur if the patient is referred for coronary artery bypass graft (CABG) surgery. In an analysis from the ACUITY trial, Ebrahimi et al. (39) examined the outcomes in 1,539 patients who underwent CABG. They found a reduction in ischemic events (12.7% vs. 17.3%, p = 0.01), without an increase in bleeding. Importantly, in the trial, a 5-day washout period was recommended, and there was an increased rate of transfusion in those that had early CABG (<5 days) compared with those who had late CABG.

Stress cardiomyopathy.   Abraham et al. (40) describe a new variant of the Tako-tsubo syndrome involving 9 patients who developed transient left ventricular dysfunction in the setting of epinephrine or dobutamine infusion. The findings are important in strengthening the evidence that catecholamines are important in the pathogenesis of stress cardiomyopathy, and also have implications in various scenarios in which pressors are infused, such as post-surgery and in sepsis.

Hypertension.   The field of arterial stiffness has emerged as central to the understanding of hypertension as well as aging. Protogerou et al. (41) evaluated 375 patients with hypertension in the REASON (Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind) study of atenolol versus perindopril/indapamide. After a year of treatment, those in the upper tertile of arterial stiffness had the lowest response to therapy in terms of systolic blood pressure control, independent of age, sex, mean blood pressure, and cardiovascular risk factors. In an accompanying editorial, Williams (42) highlights that subtle early damage may set the stage for a vicious cycle in which increasing arterial stiffness leads not only to more hypertension, but also to more stiffening of the aorta as the damage increases. The superiority of central arterial pressure by radial applanation tonometry rather than brachial pressure in predicting cardiovascular outcomes was highlighted by Roman et al. (43) using data from the Strong Heart Study. Central pulse pressure of 50 mm Hg or greater predicted cardiovascular outcomes in both men and women.

Although data from randomized clinical trials have cast doubt on the role of beta-blockers in the treatment of hypertension, it has been assumed that they would have particular utility in patients with increased heart rate. In an analysis of the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), Poulter et al. (44) showed that patients with higher baseline heart rate still fared better with an amlodipine-based therapy than an atenolol-based therapy. Lavie, Messerli, and Milani, in an accompanying editorial (45) conclude that beta-blockers, particularly the nonvasodilating beta-blockers, should not be used in the first-line therapy of hypertension.

In an interesting analysis from the CAFE (Conduit Artery Function Evaluation) substudy of the ASCOT trial, Williams et al. (46) demonstrated that heart rate lowering with beta-blocker itself is inversely associated with central aortic systolic and pulse pressures. The underlying mechanism appeared to be increased wave reflection at lower heart rates. That increased wave reflection is an important determinant of increased pulse pressure and was further established in a twin study from the United Kingdom by Cecelja et al. (47). Focusing on women age 21 to 81 years, the investigators determined that augmentation pressure, a measure of wave reflection, was highly heritable and correlates with the ratio of distal to proximal arterial diameters, a measure of arterial dimension mismatch.

Pre-operative assessment.   Randomized studies to date have not confirmed an advantage to routine angiography prior to vascular surgery. Monaco et al. (48) studied 208 patients referred for major vascular surgery, with a Lee's revised cardiac risk index (RCRI) of at least 2, randomized to angiography based on noninvasive testing versus routine angiography in all. The invasive strategy resulted in a revascularization rate of 58.1% versus 40.1%. Major adverse cardiovascular events were similar during the vascular surgery hospitalization, but long-term survival and cardiovascular events (at 58 ± 17 months) were improved in the group that underwent routine invasive angiography. In an accompanying editorial, Landesberg and Mosseri (49) point out that more patients in the invasive group underwent CABG, which while not statistically significant, may have led to better long-term outcomes. The lack of short-term benefit supports the noninvasive approach as acceptable, but the long-term benefit of the invasive approach highlights the extensive overlap between peripheral arterial disease and coronary disease.

In order to determine the effect of ramipril versus rosiglitazone in patients with impaired glucose tolerance or impaired fasting glucose, Lonn et al. (50) performed the STARR (STudy of Atherosclerosis with Ramipril and Rosiglitazone) by obtaining measurements of carotid medial thickness by ultrasound. They randomized 1,425 patients for follow-up of 3 years. The results showed that there were no statistically significantly differences between ramipril or rosiglitazone and placebo patients with regard to the primary end point of maximal carotid intima-media thickness, although there was a trend toward an improved outcome with rosiglitazone. The secondary end point of mean far wall left and right common carotid intima-media thickness was significantly reduced by rosiglitazone. In an accompanying editorial, Kaski and Cockerill (51) indicate that, despite the beneficial actions of thiazolidinedione shown in prior studies, the real beneficial effects of these agents remain uncertain.

The role of bone marrow cell transplantation remains uncertain. Yousef et al. (52) compared 62 patients with acute myocardial infarction (AMI) who underwent intracoronary autologous bone marrow transplantation 7 days after AMI to 62 patients with comparable setting. Three months after bone marrow cell therapy, there was a significant improvement in ejection fraction and stroke volume index in the treated patients, and infarct size was reduced by 8%. In addition, decreases of normal heart rate variability, late potentials, and ectopic beats were observed in patients receiving the bone marrow cell therapy. Sixty months after the therapy, the parameters initially observed were stable, and the exercise capacity of treated patients was significantly augmented in comparison with controls. Although a small study, one of many, this long-term 5-year follow-up was encouraging in showing some suggestive evidence that bone marrow cell transplantation may be of sustained benefit in patients with AMI.

Prasugrel produced more active and consistent antiplatelet effects compared with clopidogrel in the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) (53). However, the safety of a more effective oral antiplatelet regimen might be compromised in the setting of GP IIb/IIIa inhibition. In a substudy from the TRITON–TIMI 38 trial, the greater efficacy of prasugrel vs. clopidogrel was not diminished in the presence of GP IIb/IIIa inhibition and bleeding risk was not increased with the combination of prasugrel and GP IIb/IIIa inhibition. These findings suggest that prasugrel can be safely administered to patients undergoing coronary intervention who receive GP IIb/IIIa inhibitors.

One of the major clinical applications for computed tomography (CT) angiography has been in the early triage of patients with acute chest pain. Hoffmann and colleagues reported the results of the ROMICAT (Rule Out Myocardial Infarction Using Computer Assisted Tomography) study in which they evaluated the use of CT angiography in low-risk patients with acute chest pain syndromes (54). A total of 368 patients were enrolled in this randomized prospective trial, 81% of whom had either nonobstructive or no coronary disease. Sensitivity and negative predictive values for ACS of atherosclerosis on CT angiography were 100%, but sensitivity of the presence of plaque for ACS was only 54%. Both the presence and severity of coronary plaque independently predicted ACS and was incremental to the Thrombolysis In Myocardial Infarction risk score. In an accompanying editorial, Hlatky (55) opines that CT angiography in low-risk patients with chest pain in the emergency department is a promising technique. However, he points out that it remains to be documented whether this technology will result in improved outcomes.

Hypertrophic cardiomyopathy.   This year, we had a focus issue devoted to hypertrophic cardiomyopathy. Maron et al. (56) provided a prospective on the 50-year history of left ventricular outflow obstruction in hypertrophic cardiomyopathy. They indicate that despite the many debates over the years, data now unequivocally support the presence of subaortic obstruction as true impedance to left ventricular (LV) outflow, and provides a target for suitable therapy. In an accompanying article, Bos et al. (57) discuss the diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. They indicate that this is a rapidly evolving area with nearly 20 susceptibility genes having been identified. They point out that the prevalence of hypertrophic cardiomyopathy among patients with the 9 associated myofilament-encoding diseases is 35% to 65%. Prognostic information is evolving from these various genes, and the potential role in screening families is discussed. At the current time, it is clear that the genotype/phenotype correlations are essential.

The outcome of patients with mildly symptomatic or asymptomatic obstructive hypertrophic cardiomyopathy has been uncertain. Sorajja et al. (58) evaluated 544 consecutive adult patients who were free of severe cardiac symptoms and were followed for a median of 9 years. They observed that these patients have only a slightly excess mortality, although patients with markedly elevated resting outflow track gradients were at high risk of heart failure or death.

	Heart Failure

Top Interventional Cardiology Heart Failure Electrophysiology Echocardiography CT and Nuclear Imaging MRI Valvular Heart Disease Pre-Clinical Research Biomarkers Genomics/Genetics Congenital Heart Disease JACC White Papers References

 
There has been a lack of clarity about whether or not beta-blockers should be withheld from patients with aortic regurgitation. Sampat et al. (59) reviewed the records of a group of 756 patients with aortic regurgitation and related the survival rate to beta-blocker therapy. Over a mean follow-up of 4.5 years, they found that beta-blocker therapy was associated with significantly higher 1- and 5-year survival rates, even after adjusting for potential confounders. Survival benefit was also seen when the investigators performed a propensity score analysis. In an accompanying editorial, Elkayam (60) noted many patients with aortic regurgitation are candidates for beta-blockers based on the presence of other conditions. He concluded that although the results from this study should be considered to be hypothesis generating, recommendations not to use beta-blockers in aortic regurgitation should be removed.

To help further define the role of beta-blockers in the treatment of patients with heart failure with preserved ejection fraction (HFPEF), van Veldhuisen et al. (61) reported the results of a pre-specified analysis of the SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Re-hospitalization in Seniors With Heart Failure) trial. Of the 2,111 patients included in the SENIORS trial, 1,359 (64%) had impaired EF (<35%) and 752 (36%) had preserved EF. Over an average 21-month follow-up period, nebivolol treatment was associated with an HR for the primary end point of all-cause mortality or cardiovascular hospitalizations of 0.86 in patients with impaired EF and 0.81 in patients with preserved EF. There was no significant interaction of EF; the investigators concluded that the effects of nebivolol in elderly heart failure patients was similar in those with impaired and preserved EF.

Beta-blockers are a pharmacologically heterogeneous group of drugs, and a study by Rozec et al. (62) helps to further differentiate nebivolol, a beta₁-selective adrenergic blocker, which also causes nitric oxide-mediated vasodilation, from other drugs in this class. The investigators evaluated the effects of nebivolol on developed peak tension in endomyocardial biopsy specimens obtained from nonrejecting human transplanted hearts. They found that nebivolol-induced dose-dependent reductions in peak tension were similar to that seen with a preferential beta₃-adrenergic agonist. The effects of the drug were not inhibited by nadolol, a beta_1,2-adrenergic antagonist, but were reduced by use of either a selective beta₃-adrenergic antagonist or a nitric oxide synthase inhibitor. The investigators concluded that nebivolol activated the beta₃-adrenergic receptor in the human ventricle and that the nitric oxide-induced negative inotropic effects along with previously described coronary microvessel vasodilation could improve myocardial energetics. In an accompany editorial, Balligand surmised that over time the beta₃-adrenergic blocking properties of nebivolol along with its described antioxidant effects might favorably affect cardiac remodeling and that this was a possible explanation for the benefits of the drug that were demonstrated in the SENIORS trial (63).

Previous therapies for patients with HFPEF have not been directed towards underlying pathophysiologic mechanisms. Since abnormal collagen metabolism was a feature of this patient population, Mak et al. (64) performed a randomized controlled trial to assess the effects of selective aldosterone antagonism on biomarkers of collagen turnover, inflammation, and Doppler indexes of diastolic function in patients with HFPEF. They found that procollagen type III and I amino-terminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha levels increased in the control group over time. Although eplerenone had no significant impact on any of the biomarkers over the first 6 months, it significantly attenuated the increase in procollagen type III amino-terminal peptide at 12 months. Eplerenone had modest effects on Doppler measures of diastolic function. The results provide some indication that blocking the effects of aldosterone may have a role in the management of this patient population.

Recurrent hospitalizations remain an important and growing problem in the management of heart failure patients. Dunlay et al. (65) provided an interesting community perspective on this issue by describing the lifetime burden and risk factors for hospitalization following heart failure diagnosis. Studying 1,077 Olmsted County patients diagnosed with heart failure between 1987 and 2006, they found 83.1% were hospitalized at least once and that 66.9%, 53.6%, and 42.6% were hospitalized 2, 3, and 4 times, respectively. Of particular note was that noncardiovascular causes accounted for well over one-half (61.9%) of the hospitalizations. The investigators reported that male sex, presence of chronic obstructive pulmonary disease, anemia, and a creatinine clearance <30 ml/min were independent predictors of hospitalization. The investigators concluded that the high rate of noncardiovascular causes of hospitalization in this population as well as the association with comorbid conditions could provide a basis for therapeutic strategies designed to prevent hospitalizations. This study focused on outcomes in heart failure patients regardless of whether the diagnosis was made in the in- or out-patient setting and emphasizes the importance of comorbidities and noncardiovascular conditions in determining hospitalization rates in this population.

In an attempt to explain the heterogeneity in therapeutic response of heart failure patients to beta-blockers, Cresci et al. (66) performed a prospective longitudinal study examining the impact on long-term survival of functional polymorphisms in the genes encoding beta₁-adrenergic receptors (ADRB1), and in G-protein receptor kinase 5 (GRK5), a gene that regulates beta-adrenergic receptor signaling. The cohort of 2,460 patients contained 711 African Americans. Patients were genotyped for ADRB1 Arg389>Gly and GRK5 Gln41>Leu polymorphisms which are more prominent in African Americans. They found that beta-blockers increased survival in Caucasians, but not in African Americans; African Americans with ADRB1 Gly389Gly GRK5 Gln41Gln had a similar survival benefit with beta-blocker therapy as did Caucasians with the same genotype. From these results, the investigators concluded that differences caused by beta-adrenergic receptor signaling pathway gene polymorphisms and not race were the major factors contributing to differences in the effects of beta-blockers between Caucasian and African American heart failure patients.

To better understand the pathophysiology of the cardiorenal syndrome, Mullens et al. (67) evaluated a cohort of 145 consecutive patients with advanced decompensated heart failure (ADHF) who had a pulmonary artery catheter placed to help guide therapy. They found that 40% developed evidence of worsening renal function (WRF) defined as an increase of serum creatinine 0.3 mg/dl during hospitalization. These patients had a greater central venous pressure (CVP) both before and after treatment than did the patients who did not develop WRF. Patients in whom CVP was reduced to 8 mm Hg were significantly less likely to develop WRF. CVP was able to stratify risk for WRF across the spectrum of blood pressure, pulmonary capillary wedge pressure, cardiac index, and estimated glomerular filtration rate. The investigators concluded that elevated CVP is the most important hemodynamic risk factor for developing WRF in patients with ADHF. The results imply that increased attention to lowering CVP should be a goal of the heart failure hospitalization. In an accompanying editorial, Jessup and Costanzo (68) commented that more precise information about CVP and renal function from prospective trials is needed and that studies designed to assess the effects of lowering of CVP on renal function and outcomes were needed.

Currently available pulsatile devices have limitations in design including large pump size, requirement for extensive surgical dissection for implant, and large body habitus, need for a large-diameter percutaneous venting lead, audible pump operation, and a high incidence of reoperation for device infection or malfunction. Continuous flow rotary devices are an alternative that have the potential to be smaller in size and more reliable. Pagani et al. (69) reported on the outcomes in 281 patients who were urgently listed for transplantation who underwent implantation of the HeartMate II continuous flow rotary device. After 18 months of follow-up, 222 (79%) either underwent transplantation, had the left ventricular assist device (LVAD) removed after recovery, or had ongoing LVAD support. At 6 months, there were significant improvements in functional class and 6-min walk test distance and in quality of life. Major adverse events included bleeding, stroke, right heart failure, and percutaneous lead infection. Pump thrombosis occurred in 4 patients. The benefits combined with a very low rate of device malfunction or infection support the concept that continuous-flow rotary pumps are superior to pulsatile devices in patients listed for transplantation.

Ypenburg et al. (70) demonstrated that extensive morphological changes occur within 6 months following cardiac resynchronization therapy (CRT). Reverse remodeling, measured as the change in LV systolic volume, strongly predicted hospitalization-free 2-year survival following CRT. These findings enable the clinician to decide which patients are likely to improve and which are likely to need additional interventions such as transplantation following CRT.

	Electrophysiology

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Marcus et al. (71) reviewed the North American ARVC (Arrhythmogenic Right Ventricular Cardiomyopathy) Registry to assess the efficacy of antiarrhythmic drugs in all subjects with an implantable cardioverter-defibrillator (ICD). Ninety-five patients were followed for 480 ± 389 days. The authors found that beta-blockers were neither beneficial nor harmful, that sotalol was not effective in preventing ventricular arrhythmias, and that amiodarone showed superior efficacy compared with either beta-blockers or sotalol. Potential limitations of this study include the small number of patients receiving amiodarone, and that previous studies (72,73) showing that sotalol prevented ventricular arrhythmias used electrophysiology testing to guide therapy. The authors concluded that, since no patients died during follow up, use of an ICD was effective therapy in preventing sudden death in these high-risk patients. Haissaguerre et al. (74) studied 122 patients with a history of idiopathic ventricular fibrillation (VF) and early inferolateral repolarization on electrocardiogram (ECG); 33 had a history of more than 3 recurrent VF episodes and were compared with the 89 who did not. Patients with multiple VF had a higher incidence of prior syncope, a higher incidence of inducible VF during programmed stimulation, and a higher amplitude of J point on baseline ECG. Electrical storm, seen in 16 patients, was unresponsive to beta-blockers and calcium-channel blockers, and class 1b, 1c, and 3 antiarrhythmic drugs, including amiodarone. Intravenous isoproterenol suppressed electrical storm acutely in 100% of patients (n = 7) to whom it was administered, and oral quinidine prevented recurrence of VF chronically in 100% of patients (n = 9) to whom it was given over 25 ± 18 months follow-up. The authors concluded that early repolarization in the inferior and left pre-cordial ECG leads is a distinct clinical entity associated with sudden death (75). In addition, the authors noted that this syndrome accounted for 31% of aborted, unexplained sudden death in their population. The underlying mechanism of arrhythmia may be related to action potential heterogeneity across the ventricular wall at the end of phase 1 depolarization (due in part to differences in Ito current across the ventricular wall), which is uniquely responsive to quinidine. Although this condition has some similarities to Brugada syndrome, it differs in ECG abnormalities, the lack of sensitivity to sodium channel blockers, and lack of associated conduction defect or SCN5A mutation.

Haqqani et al. (76) performed detailed electroanatomic mapping of the LV endocardium in 17 ischemic cardiomyopathy (ICM) patients without clinical sustained monomorphic ventricular tachycardia (SMVT) and in 17 ICM patients with clinical SMVT, in order to identify the possible underlying differences in electrophysiologic substrate. They observed no difference in baseline LV diameter, LVEF, infarct territory, or time from infarction, but did observe that control patients without clinical SMVT had smaller total low-voltage (1.5 mV) area (30% vs. 55%), smaller very low-voltage (<0.5 mV) area (7.3% vs. 29%), higher mean voltage of low-voltage zones, fewer fractionated, isolated, and very late potentials with lower density of these scar-related electrograms per unit low-voltage area, less SMVT inducibility, and fewer potential conducting channels within dense scar and adjacent to the mitral valve annulus. The authors concluded, therefore, that ICM patients with SMVT had an underlying electrophysiologic substrate that promoted the development of re-entrant arrhythmias, despite having similar overall ventricular function compared with ICM patients with SMVT. These findings show that inducibility of SMVT in patients with similar EF identifies patients at particularly high risk of sudden death, and also suggest that noninvasive means to identify the presence of extensive scarring with a high density of areas of slow conduction and myocardial channels capable of forming re-entry circuits should be further studied. These findings also suggest that the current approach of extensive ablation of myocardial channels between areas of dense scar or between scar and the mitral valve annulus, even in sinus rhythm, may have a valid mechanism for efficacy.

Myerburg et al. (77) provide an in-depth review of the major randomized ICD trials for primary and secondary prevention of sudden death in patients with ischemic and nonischemic heart disease. By summarizing the results and limitations of these trials, and their impact on clinical practice, this review is helpful to the reader in implementing these findings in their clinical practice. The authors also discuss in detail the role of ICDs in patients with somewhat less common arrhythmogenic disorders, including myocarditis, infiltrative diseases, and inherited disorders including ARVC/arrhythmogenic right ventricular dysplasia (ARVD) and the channelopathies, despite the relative lack of randomized clinical trials in many of these rare conditions. In addition, the authors provide a rather sobering perspective on the future of how these trials will affect the practice of sudden death prevention, particularly ICD implantation, in light of the economic impact that such practice will have. The authors recommend that further research is required for better risk prediction, and particularly, dynamic risk prediction, in order to yield a greater overall benefit of ICD implantation in the larger, yet lower risk, populations, including those at high risk for coronary artery disease, but no prior event, or the general population. Finally, the authors note that by identifying additional funding for such research, a clear limitation identified in earlier studies, and by creating a formal interaction between the research and clinical enterprises, especially in view of the large impact the former has on the latter, that even modest increments in funding would potentially have a large economic impact on clinical practice by providing more comprehensive data and clinically useful guidelines.

Dizon et al. (78) reviewed the records of 174 consecutive heart transplant and 122 double-lung transplant patients in whom surgery was performed over a period of 3.5 years, for evidence of atrial fibrillation (AF) as confirmed on ECG by an electrophysiologist. Clinical variables evaluated from the perioperative time period and at the time of arrhythmia occurrence included biopsy results, immunosuppressive regimens, and echocardiographic measurements. In the heart transplant group (A) 4.6% had AF, whereas in the lung transplant group (B), 18.9% had AF (p < 0.001). The incidence of AF in a comparison group of 131 patients with normal LV function who underwent CABG was 19.8%. Immunosuppressive regimens and clinical variables were similar for both groups. However, echocardiography revealed no significant cardiac abnormalities in 74% of group B patients compared with 25% of group A patients (p < 0.05), and 78% of biopsy results in group B patients were normal, whereas only 25% of group A patients had normal biopsies (p < 0.05). Thus, AF is uncommon in heart transplant recipients, occurring mainly in the setting of myocardial dysfunction and graft rejection, whereas AF is more common after lung transplantation despite the absence of graft rejection and cardiac dysfunction. The authors, therefore, conclude that PCI alone cannot explain the discrepancy in AF incidence between heart and double-lung transplant recipients, but that cardiac autonomic denervation may have a protective effect for heart transplant patients in the post-operative setting. The role of parasympathetic nerve (vagal) stimulation has been suggested in other studies to have a potentially important role in initiation and maintenance of AF, and that vagal denervation by surgery or ablation may play an important antiarrhythmic role in prevention of AF recurrence.

Mechanisms of AF.   By definition, it has been considered that "lone atrial fibrillation" occurs in the absence of cardiac comorbidities. A study by Stiles et al. (79) challenges this notion. In 25 patients with paroxysmal lone AF, but without significant AF in the preceding week, and 25 reference patients with left-sided accessory pathways, the authors used linear multipolar catheters to study effective refractory period, conduction time, and conduction characteristics at multiple left and right atrial sites. Compared to "reference" patients, those with lone AF demonstrated larger atrial volumes, longer refractory periods, longer conduction times, slower conduction velocity along the linear catheters, a greater proportion of fractionated ECGs, abnormal sinus node function, and lower voltage. Thus, these results demonstrate a distinct atrial "substrate" even in patients with paroxysmal lone AF. However, given that patients with lone AF do enjoy a relatively benign prognosis, further studies should determine whether their substrate differs from, or is simply less marked than, that observed in AF patients with cardiac comorbidities, and define the relationship between these substrates. These and other issues are discussed in the accompanying editorial (80).

A new antiarrhythmic agent for the treatment of atrial fibrillation was introduced in the form of dronedarone. Piccini et al. (81) did a comparative efficacy study of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with AF from all available randomized control trial data. They compared 4 placebo-controlled trials of dronedarone with 4 placebo-controlled trials of amiodarone, and 1 direct comparison between the 2 agents. They found that amiodarone was superior to dronedarone (OR: 0.49) for the prevention of recurrent AF, but a concomitant trend toward greater all-cause mortality (OR: 1.6) and greater overall adverse events requiring drug discontinuation (OR: 1.81) with amiodarone. They estimated that for every 1,000 patients treated with dronedarone, there would be 228 more AF recurrences in exchange for 9.6 fewer deaths and 62 fewer adverse events with amiodarone. In an accompanying editorial, Chan et al. (82) indicate that these data remain hypothesis generating, that no definitive conclusion can be reached regarding the comparison of these agents, and that clinicians will have to employ their best judgment in using these agents.

ICD therapy.   Several studies in the Journal this year studied the impact of psychological factors on outcome in ICD recipients. van den Broek et al. (83) examined the combination of anxiety, depression, and distressed or type D personality as predictors for ventricular arrhythmias in patients with ICDs. In 391 ICD recipients, ventricular arrhythmias occurred in 19% of patients. Notably, anxious patients with a type D personality had a significantly increased rate of ventricular arrhythmias (29.6%) compared with other ICD patients (16.9%; HR: 1.89). However, increased symptoms of depression or anxiety did not predict arrhythmias. On multivariate analysis, anxious type D patients (HR: 1.72) and secondary prevention patients (HR: 1.91) were at the greatest risk for ventricular arrhythmias. These results suggest that anxious type D patients should be offered additional behavioral support after ICD implantation. In a separate study, Goldstein et al. (84) addressed the important but relatively unstudied issue of whether the topic of preventing potentially traumatic ICD shocks via ICD deactivation is discussed in patients near end of life. Internists and geriatricians were found to be less positive than electrophysiologists that their patients understood end-of-life choices regarding ICD deactivation. The most likely barrier to ICD deactivation was a lack of patient awareness of this possibility. This study reinforces the fact that patient education of device therapy should be comprehensive and change over time as an individual's disease progresses.

There is increasing appreciation and concern for the potential side effects of ICD therapy. For instance, studies by Poole et al. (85) from the SCD-HefT (Sudden Cardiac Death in Heart Failure Trial) database and by Daubert et al. (86) from the MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) database in the Journal in 2008, suggest that patients who receive ICD shocks have a worse subsequent outcome than those who receive no-shock ICD therapy (i.e., antitachycardia pacing) or no ICD therapy, even when shocks are successful. An intriguing report by Tereshchenko et al. (87) showed that ICD therapy may result in detectable local injury current in the ICD lead ventricular electrogram, hinting at a potential mechanism for adverse outcome. Over a mean follow up of 29 ± 15 months, the authors detected a local injury current (LIC) on a right ventricular (RV) electrogram in 106 of 390 patients, and 40 patients suffered heart failure exacerbations. On multivariate analysis, patients with LIC were significantly more likely to die or to be hospitalized for heart failure (HR: 2.69). These results suggest a mechanism to explain the potential adverse outcome associated with ICD shock therapy, and motivate additional strategies to reduce ICD shocks via ablation (see the following text). These results may also help generate hypotheses linking heart failure with local myocardial injury unassociated with elevated serum cardiac biomarkers.

Mechanisms of ventricular tachycardia (VT).   The multicenter SMASH-VT (Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia) trial (88) demonstrated that ablation reduces the incidence of subsequent ICD therapy in patients with cardiomyopathy. Cano et al. (89) performed electroanatomic mapping of the epicardium and endocardium in 22 patients with LV nonischemic cardiomyopathy and suspected epicardial VT, compared to similar mapping in 8 patients with normal hearts and idiopathic VT. The authors found confluent low-voltage areas in 18 epicardial (82%) and 12 endocardial (54%) maps, typically at the basal lateral LV. In the 18 patients with epicardial VT, low-voltage area was greater on the epicardium than endocardium. Ablation targeted to endocardial and epicardial low-voltage areas eliminated VT in 71% of patients at 18 months of follow-up. These results guide future ablation approaches to patients with nonischemic cardiomyopathy and suspected VT of epicardial origin, and also raise mechanistic questions over why the basolateral LV and epicardium are so commonly affected, as discussed in the accompanying editorial (90).

Long QT syndrome (LQTS).   LQTS and its link to life-threatening ventricular arrhythmias continues to be an active area of investigation. Clinically, Kirchhof et al. (91) systematically studied ECG tracings of patients with acquired and congenital LQTS to provide a clinical index of premature ventricular complexes that initiated torsades de pointes, versus those that did not. The authors studied ECG recordings from 35 LQTS patients with torsades de pointes, from 40 patients with normal QT intervals and premature ventricular complexes (PVCs), and of PVCs unrelated to torsades in 24/35 LQTS patients. The authors found that abnormal T–U waves (6.2 ± 0.9 mm) directly preceded torsades in 34/35 LQTS patients, and were larger than T-wave amplitude (2.8 ± 0.2 mm) in control patients and larger than the largest T–U-wave in LQTS without torsades (4.7 ± 0.8 mm). Moreover, the QRS duration of the first torsades beat (175 ± 12 ms) was longer than in control PVCs (145 ± 4 ms) and in PVCs in LQTS patients not related to torsades de pointes (138 ± 22 ms). These data systematically demonstrate that giant T–U waves ominously portend the initiation of torsades de pointes in LQTS patients, and are absent with PVCs that do not initiate torsades in LQTS patients, or for PVCs in patients with other heart disease.

Mechanistically, several studies have examined genetic variants that modify the LQTS disease phenotype. Nishio et al. (92) studied whether D85N, a polymorphism in the KCNE1 gene that encodes the beta-subunit of the cardiac voltage-gated K+ channel, is a gene variant that may cause LQTS rather than simply modifying the LQTS phenotype. The authors performed genetic screening in 317 LQTS probands, examined D85N in these patients and in 496 healthy control subjects, and conducted biophysical assays for the D85N variant in mammalian cells. The authors found that allele frequency for D85N carriers was 3.9% among LQTS probands compared with 0.81% in healthy people. Notably, after excluding 7 of 23 heterozygous carriers with additional LQTS-related gene mutations, and 3 female subjects in whom other factors explained their symptoms, the prevalence of D85N in LQTS probands remained significantly higher than in controls. In a heterologous expression study with Chinese hamster ovarian cells, KCNE1-D85N was found to exert significant loss-of-function effects on both KCNQ1- and KCNH2-encoded channel currents, supporting its mechanistic role in actually causing LQTS. Thus, these results support the argument that a myriad of genetic "variants" may cause LQTS in selected patients rather than simply modifying the phenotype of existent LQTS. These and other issues are discussed in the accompanying editorial (93).

Potentially arrhythmic autonomic modulation of the QT interval was studied by Piccirillo et al. (94) in dogs with pacing-induced tachycardia heart failure. The authors compared autonomic nerve activity, measured continuously with implanted stellate-ganglion data transmitters in 6 animals, with the ECG QT variability index, a previously described index of temporal cardiac repolarization dispersion that predicts sudden death in heart failure patients (see, for instance, Haigney et al. [95]). The authors examined integrated left stellate-ganglion nervous activity, integrated vagus nerve activity for 36 ECG segments recorded at baseline and 36 after induced congestive heart failure (CHF). Segments were arbitrarily identified as containing low or high sympathetic activity. In the high sympathetic activity subgroup, QT intervals and the QT variability index increased from baseline to CHF whereas, in the low sympathetic activity subgroup, they remained unchanged. Baseline QT variability index correlated inversely with integrated vagus nerve activity, but during heart failure, QT variability index correlated directly with integrated left stellate-ganglion nervous activity. The authors conclude that, during heart failure, sympathetic activation is associated with potentially pro-arrhythmic increases in the QT interval and QT variability index. Conversely, under normal conditions, there was no relationship between sympathetic activation and QT variables. These results shed light on the mechanisms linking autonomic nervous activity with sudden death in heart failure patients, and also inform the noninvasive identification of such patients using ECG QT indexes.

Other inherited arrhythmic syndromes.   Interest in inherited arrhythmic syndromes continues to grow with our familiarity with and recognition of affected individuals in the clinic. A series of papers in the Journal this year focused on the clinicopathophysiological spectrum encompassed by clinical ARVC. Pieroni et al. (96) studied 30 consecutive patients with clinical criteria for ARVC via endomyocardial biopsy at low-voltage ventricular regions identified from 3-dimensional electroanatomic mapping. They found abnormal voltage maps (considered to indicate myocardial replacement by scar, fibrosis, and/or fat) in 29 patients. Histology and immunohistochemistry of said biopsies confirmed the diagnosis of ARVC in 15 patients, and revealed active myocarditis per the Dallas criteria in 15 patients. In a secondary analyses, the authors suggest that patients with myocarditis had fewer arrhythmic events on follow-up. Further studies should determine whether myocarditis in patients with clinical ARVC is secondary to ARVC, a pathophysiologic process that may occur en route to classical fibrofatty replacement, or a distinct entity.

A study by Dalal et al. (97) added important information to the ongoing debate on the extent of left ventricular involvement in ARVC, and attempted to develop more specific diagnostic criteria for the disease. In 38 family members of 12 desmosomal mutation-carrying ARVD/ARVC probands, the authors performed genotyping and cardiac magnetic resonance imaging (CMR). Twenty-five individuals had identified mutations. RV abnormalities were associated with the presence of mutation(s) and with clinical disease severity. Conversely, LV abnormalities were limited to intramyocardial fat in 4 individuals, mostly mutation carriers. CMR confirmed a focal "crinkling" of the RV outflow tract and subtricuspid regions as previously observed, dubbed the "accordion sign" by these authors, in 60% of mutation carriers. The prevalence of this sign increased with the clinical severity (by task force criteria). Thus, in these patients in whom LV involvement was uncommon, the CMR finding of the accordion sign tracked ARVC disease severity. These results may help to improve clinical diagnosis of this ARVC, and should be used to test whether the presence of these CMR findings guide prognosis.

The role of sleep-disorder breathing in triggering nocturnal arrhythmias remains controversial. To study this question, Monahan et al. (98) screened the polysomnograms from 2,816 patients in the Sleep Heart Health Study for the presence of paroxysmal AF and nonsustained VT. They found that the odds of an arrhythmia occurring after a respiratory disturbance were nearly 18 times higher than that occurring after normal breathing. The absolute rate of arrhythmia associated with sleep-disorder breathing was low. Neither hypoxia nor arousals alone increased arrhythmias. Although infrequent, in a related study, Eleid et al. (99) demonstrated a high prevalence of abnormal nocturnal oximetry in patients with hypertrophic cardiomyopathy, and that patients with abnormal oximetry were more symptomatic than their hypertrophic cardiomyopathy colleagues without disordered breathing. In an accompanying editorial, Wilcox and Semsarian (100) indicate that the link between obstructive sleep apnea and clinical cardiovascular disorders including AF and hypertrophic cardiomyopathy is rational based on the known pathophysiology and may provide a clue to effective therapy in some patients.

The treatment of ventricular premature beats (VPBs) with drugs as a strategy to prevent VF has had a catastrophic history as illustrated by the CAST (Cardiac Arrhythmia Suppression Trial). Knecht et al. (101) show promising long-term results using ablation of short-coupled VPBs, a finding that potentially reopens the concept of suppression of VPBs as a strategy for control of VF. By avoiding the toxicity of antiarrhythmic therapy, this alternate approach is promising in selected patients.

	Echocardiography

Top Interventional Cardiology Heart Failure Electrophysiology Echocardiography CT and Nuclear Imaging MRI Valvular Heart Disease Pre-Clinical Research Biomarkers Genomics/Genetics Congenital Heart Disease JACC White Papers References

 
Aside from the standard chest X-ray, echocardiography is the most mature of all of the imaging modalities. It is well integrated into the daily care of patients with cardiovascular disease. However, a number of new technologies in applications continue to evolve.

The prognostic value of exercise echocardiography was explored in 4,004 consecutive patients with a normal exercise test (102). In these patients, the change in wall motion score index was an independent predictor of mortality, which yielded incremental value over the clinical, resting echocardiographic and exercise hemodynamic data. Conversely, an accompanying editorial emphasized that a normal exercise echocardiogram predicted an annual cardiac death or infarction rate of only 0.84% and 0.64% (103).

Three-dimensional echocardiography is increasingly used in clinical practice to evaluate valvular problems (104,105). In 18 patients with previous mitral annuloplasty or valve replacement, ring or valve dehiscence was evaluated with real-time 3-dimensional transesophageal echocardiography (106), showing precise definition of the dehisced segment and origin of the mitral regurgitation.

The value of diastolic strain changes following exercise as a marker of coronary artery disease was assessed in 162 patients with stable angina (107). The mean strain imaging diastolic index decreased from 78.0 ± 9.7% to 27.6 ± 16.0% (p < 0.0001) 5 min after exercise in regions perfused by coronary arteries with stenoses 50% of the luminal diameter. Possibly, this index provides a very sensitive marker of coronary artery disease, since diastolic function abnormalities occur early during the ischemic cascade (108).

Assessment of cardiac deformation.   Myocardial defamation, usually based upon measurements of strain, can depict myocardial performance independent of variables of overall cardiac motion and tethering to adjacent myocardium inherent in endocardial motion. Utilizing tissue Doppler and speckle tracking methodologies, echocardiography can delineate strain and myocardial rotation as well as ventricular torsion. Ishii et al. (109) applied speckle tracking techniques to transverse strain to study the prevalence and duration of diastolic dysfunction following myocardial ischemia induced in the setting of angioplasty. They observed that strain became abnormal during both systole and the first one-third of diastole during coronary occlusion in the affected segments, but that only diastolic strain remained abnormal following reperfusion. Diastolic strain was decreased for 24 h, establishing the potential for persistent diastolic dysfunction (stunning) to detect post-ischemic memory.

Cho et al. (110) compared global 2-dimensional strain to standard ventricular EF to predict clinical events in 201 heart failure patients followed for 39 ± 17 months. In multivariate analysis, age and the global circumferential strain were independently associated with cardiac events, demonstrating that global circumferential strain is a more potent prognosticator of cardiac events than EF in heart failure patients. In an accompanying editorial, Lafitte (111) pointed out that measurement of circumferential strain may be limited in quality and reproducibility, and that a multicriteria echocardiographic analysis of LV function remains attractive in assessing patients with heart disease. In another study, Tann et al. (112) applied ultrasound measures of defamation to study the pathophysiology of heart failure with normal EF (diastolic failure) at rest and during exercise. As compared with controls, they observed that systolic longitudinal and radial strain, mitral annular velocities, and apical rotation were lower in the diastolic failure patients at rest and failed to increase normally with exercise. They concluded that widespread abnormalities of both systolic and diastolic defamation are present in the setting of heart failure with normal EF and are exposed with exercise. In an accompanying editorial, Marwick (113) pointed out that this study demonstrated that the abnormalities of velocity, rotation, and defamation resulted in an abnormal twisting of the apex with delayed untwisting resulting in reduced suction in increased end-diastolic pressure on exercise. These data were attractive in providing a unifying concept of systolic and diastolic abnormalities accounting for heart failure in the setting of a normal EF.

Contrast echocardiography.   Although nitric oxide is a gas with substantial beneficial potential, it is extremely difficult to deliver systemically. Therefore, Huang et al. (114) developed a methodology to administer nitric oxide utilizing echogenic liposomes as a gas carrier. They observed that encapsulation of nitric oxide with argon reduced intimal hyperplasia by 40% in a rabbit model of carotid atherosclerosis. This study represents another step forward in the application of contrast microbubble agents to deliver therapeutic agents.

Although time–intensity curves produced by contrast echocardiography have been primarily used to study myocardial perfusion, Womack et al. (115) applied this technique to assess skeletal muscle capillary perfusion in patients with diabetes with and without microvascular complications. They obtained time–intensity curves from the forearm flexor muscles at rest and during high-intensity handgrip exertion. They observed an approximately 50% reduction in capillary recruitment at rest and 60% to 70% reduction with exertion in patients with diabetes and microvascular complications, patients who also demonstrated greater insulin resistance and whole blood viscosity. This study demonstrated a useful clinical application of contrast ultrasound to study peripheral vascular abnormalities. In an accompanying editorial, Porter (116) observed that these data demonstrate that it will be important to evaluate pathological vascular responses in the microcirculation as well as in larger vessels in diabetic patients, and contrast echocardiography is particularly well suited to this task.

Role of echo in resynchronization.   A pressing need exists to identify those patients who fulfill current indications for cardiac resynchronization who will benefit from biventricular pacing, and echocardiography has been the technique most prominently considered for this purpose. However, as reviewed by Bax and Gorcsan (117), the PROSPECT (Predictors of Response to Cardiac Resynchronization Therapy) study failed to demonstrate that echocardiography could reliably predict those patients who would benefit from resynchronization therapy. The authors reviewed the multiple variables that may have influenced the results of the PROSPECT study, including patient selection, technical issues involved in performing the studies, and the presence of myocardial scar, and the ability to pace the most dyssynchronous area of myocardium. In this same issue, Hawkins et al. (118) contributed a Viewpoint that argued that cardiac dyssynchrony identified by echo did not have a significant role in selecting patients to undergo cardiac resynchronization. However, in an accompanying commentary, Sanderson (119) argued that it was critically important to be able to identify those patients who should receive biventricular pacing, that echocardiography had shown promise in this regard, and that future studies should be directed to improving the technique so that it is more accurate. These 3 papers present well the current state of knowledge and controversy regarding the role of echo in resynchronization therapy, and seem to reach a consensus that more work is needed before echo can reliably serve in this capacity.

Intracardiac echocardiography (ICE).   The use of intracardiac imaging to guide noncoronary interventions is receiving increasing attention. This area was reviewed by Kim et al. (120) who pointed out that ICE has been the primary modality used for this purpose. Thus far, ICE has been used to guide transseptal heart catheterization, to guide catheter ablation of cardiac arrhythmias, and to assist in the percutaneous closure of atrial septal defects and patent foramen ovale as well as in the performance of mitral valvuloplasty. It would appear that ICE has achieved acceptance as a valuable tool for the performance of a variety of noncoronary cardiac interventions. (120).

	CT and Nuclear Imaging

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Various studies addressed the expanding role of cardiac CT imaging. Budoff et al. (121) used the MESA (Multi-Ethnic Study of Atherosclerosis) study to assess the predictive value of calcium scores for future events in 6,814 subjects over 3.8 years. They found calcium scores to be highly predictive of incident coronary disease, and that absolute scores were more predictive than age–sex percentile scores. Moreover, as emphasized in an accompanying editorial, these calcium scores retained their discriminative power independent of the presence/absence of traditional risk factors (122). Documentation of an elevated coronary calcium score significantly increased the chance of additional cardiac testing during follow-up in an analysis of 1,361 subjects by Shaw et al. (123). By 1 year of follow-up, 9.4% of subjects with a calcium score of 0 to 10 had 1 or more additional noninvasive tests. By contrast, among patients with calcium scores of 1,000 or more, 58.1% had further noninvasive testing, and 12.0% had coronary revascularization. Still, the presence and extent of coronary artery calcium do not necessarily indicate or exclude myocardial ischemia. Chang et al. (124) evaluated 1,126 asymptomatic subjects who had coronary artery calcium scoring with electron beam CT and nuclear perfusion imaging (single-photon emission computed tomography [SPECT]) followed for a median of 6.9 years. An abnormal SPECT result increased in parallel to an increasing calcium score from 1% in patients with a score 10 to 29% in patients with a score >400 (p < 0.001). Moreover, in patients with a normal SPECT, coronary calcium score provided incremental prognostic information with a 3.55-fold increase for any cardiac event when the score was >400 as compared with 10.

Prospective gating CT angiography can decrease radiation dose without reducing diagnostic accuracy for detecting stenoses (125). Assessment of myocardial perfusion by CT angiography enables relation of anatomic stenoses to hemodynamic. A direct comparison between SPECT and stress-rest CT perfusion imaging (average dose of 12.7 mSv) was performed in 33 patients (126). The diagnostic accuracy of CT was comparable to SPECT for detection of significant coronary artery stenoses.

In patients with coronary stents, CT imaging could define stent gaps not easily detected on invasive angiography (127), which were associated with 28% in-stent restenosis (28%). Cardiac CT can also be applied in patients receiving percutaneous aortic valve replacement, for precise assessment of prosthesis deployment (128).

Various advances in nuclear imaging were reported. Among 1,056 consecutive patients who underwent physiological exercise SPECT perfusion imaging, 473 achieved 10 metabolic equivalents without ischemic ST-segment changes during exercise; none of these had significant ischemia on SPECT (129). In these patients, it may be considered to eliminate SPECT imaging and thus save substantial costs (130).

Approximately 50% of SPECT myocardial perfusion studies are performed with vasodilator stress. Regadenoson is a selective A2A agonist (131) which can be given as an intravenous bolus at a fixed dose, with fewer side effects, including atrioventricular block and bronchospasm, and may thus further optimize pharmacological SPECT perfusion imaging. Nuclear imaging using iodine-123 metaiodobenzylguanidine provides information on cardiac adrenergic nerve activity, and abnormalities have been associated with poor outcome in heart failure patients. In 106 patients with mild-to-moderate heart failure, it was shown that abnormal tracer washout rate was predictive of sudden death, independently of LVEF (132). In these patients, signal-averaged ECG, heart rate variability, and QT dispersion were not predictive.

Positron emission tomography (PET) with N-13 ammonia was applied in 229 patients for absolute quantification of myocardial perfusion and coronary flow reserve (133). Patients with abnormal perfusion had worse outcome over a follow-up period of 5.4 years; in patients with normal perfusion, abnormal coronary flow reserve (<2.0) was associated with a significantly higher event rate and cardiac death rate. Addition of coronary flow reserve to perfusion may further improve risk stratification with PET (134). Since PET permits absolute blood flow quantification, this technique is ideal for detecting subtle abnormalities in patients with metabolic syndrome and diabetes, even in the absence of overt coronary artery disease (135). In addition to perfusion imaging, cardiac metabolism and innervation can also be quantified with PET. Furthermore, with the introduction of hybrid PET-CT systems, the integration of anatomic and physiologic imaging will become more popular over the next years (136). This concept was applied in an animal model of intramyocardial stem cell therapy, in which PET-CT was used to register and track the stem cells (labeled with the PET tracer F-18 fluorodeoxyglucose) (137). These molecular imaging techniques may aid in better understanding of the fate of stem cells after injection (138).

CT coronary angiography provides a noninvasive method to rule out obstructive coronary disease, but there are relatively few data on patient outcomes. Hoffman et al. (54) performed CT angiograms in 368 consecutive low-risk chest pain patients evaluated in the emergency department, without use of the results in clinical care. One-half of the patients were free of coronary disease and without coronary event, indicating that a negative CT angiogram has high negative predictive power in low-risk patients with acute chest pain.

Cardiac CT angiography studies also turn up incidental findings in the lungs and mediastinum, the significance of which is controversial. MacHaalany et al. (139) found 1 or more noncardiac incidental findings in 42% of 966 patients. Only 1% of patients had findings of immediate clinical significance, and a further 7% had findings that required follow-up. Over the subsequent 18 months, the cost of follow-up studies averaged $1,038 per patient, and an average of 1.1 additional CT scans. It is difficult to judge whether the cost and additional radiation exposure was justified by the small yield of clinically important findings.

Suaya et al. (140) used propensity score matching and instrumental variables methods to assess the effect of cardiac rehabilitation on mortality. Their results suggest a significant reduction of mortality due to rehabilitation, ranging from 21% to 34%, depending on the methods used. The study is important in applying several alternative methods of analysis to the same dataset, and helps to improve the methods of observational analysis.

The relationship between volume of PCI procedures and clinical outcomes has been very controversial, in part because many interventionalists perform relatively low volumes. Srinivas et al. (141) examined the relationship between volume of primary PCI procedures and the outcome of patients with AMI using data from the New York State registry. They found that the effect of physician volume on outcome was modified by the hospital volume, with the poorest outcomes found with low-volume operators in low-volume hospitals.

Readmissions of Medicare patients has drawn increased scrutiny of policymakers, who believe reducing such admissions would simultaneously decrease costs and increase quality of care. Readmissions within 30 days of a PCI procedure were found to be quite common: 15% in an analysis of a cohort of some 315,000 Medicare patients by Curtis et al. (142). A repeat revascularization procedure was performed in only 28% of these readmissions, although most of the readmissions were for cardiac indications. Clearly, more study of this issue is needed to clarify whether the readmissions reflected lower quality of care, a poor transition between inpatient and outpatient care, or simply the underlying severity of illness in these patients.

Second-hand smoke is associated with increased risk of cardiovascular disease, which is one of the major reasons for banning smoking in public places. Meyers et al. (143) analyzed 10 studies of the effects of smoking bans, report that there was a 17% lower risk of AMI in localities that banned public smoking compared with localities that did not. This study, along with a recent Institute of Medicine report, should accelerate passage of local ordinances banning public smoking.

The importance of intensive glycemic control among patients with diabetes has been controversial, with randomized studies suggesting that macrovascular outcomes may not be improved. Aguilar et al. (144) reported a provocative finding of a "U-shaped" relationship between hemoglobin A_1C levels and outcomes among patients with heart failure and diabetes. This finding adds further fuel to the fire about the optimal approach to management of patients who have both diabetes and heart disease.

	MRI

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In the field of MRI, considered by most imagers as the ultimate cardiovascular phenotyping modality, JACC published the most important breakthroughs regarding translational and clinical applications of cardiac MRI. The most important development in the field was the maturity and clinical translation of techniques based on T2 imaging to detect myocardial edema and thus characterize the total volume of myocardium at risk during coronary occlusion. The translation of these techniques to clinical cardiology has been pioneered in North America by groups working at University of Calgary (M.G. Friedrich and collaborators) and at the National Heart, Lung, and Blood Institute (A. Arai, A. Aletras, and collaborators). This year, the Calgary group published fundamental subclinical studies in JACC (145) that establish the pathophysiologic time course of myocardial edema formation and its potential use as the earlier imaging markers of myocardial injury following coronary occlusion and ischemia. The paper is accompanied by a comprehensive editorial reviewing the state of the art of T2 imaging in cardiovascular research and medicine (146).

Upstream from myocyte injury in the ischemic causation chain, magnetic resonance has been used to probe microvascular function as well as larger arterial obstruction and remodeling. Novel methods begin to find their way as promising cardiovascular applications as demonstrated in the articles by Wu et al. (147) and Anderson et al. (148). Both techniques follow the usual trail of cardiovascular magnetic resonance methods development which commonly begin deployment in vascular beds and target organs other than the coronary arteries and the heart. In the first study, continuous arterial spin-labeling perfusion MRI was used to study microvascular flow impairment associated with different degrees of peripheral artery disease (PAD). In the second, the elegant combination of arteriography, perfusion, and spectroscopy was used to demonstrate that there exists a dissociation between cellular metabolism and tissue perfusion in peripheral vascular disease. The accompanying editorial by Dewey (149) puts in perspective the findings from the latter report in the evaluation of patients with peripheral vascular disease. In terms of vascular imaging, MR angiography inches its way to study the coronaries in a clinically meaningful manner as 3.0-T systems become available primarily for neurologic applications. In the last year, JACC published an important paper by Yang et al. (150) showing the benefits of harnessing the extra signal-to-noise margin created by MR 3.0-T imaging to enhance the power to evaluate the coronary arteries. The accompanying editorial by Sibley and Bluemke (151) briefly reviews the "state of the art" of coronary imaging by MRI and highlights its potential application to investigate coronary remodeling in population studies such as the MESA (152).

This year, the clinical value of MRI in patients with heart failure has become well established. As the gold-standard method to assess cardiac morphology and tissue characteristics, the value of MRI in heart failure was illustrated by various efforts at characterizing hypertrophic cardiomyopathy (153), the beneficial effects of pronounced weight reduction by bariatric surgery and diet (154) as well as cardiac energetics in heart failure with preserved systolic function, probed by MR spectroscopy (155). The role of MRI in heart failure was comprehensively reviewed by the Oxford group (156), including the clinical methods of tissue characterization by contrast enhancement in the study of dilated, hypertrophic, and restrictive cardiovascular disease. In this regard, the risk of nephrogenic systemic fibrosis secondary to gadolinium contrast utilization in patients with renal impairment was also reviewed by Kribben et al. (157), given the increasing importance of contrast enhanced MRI methods to the cardiologist's current clinical practice. Finally, safe utilization of MRI in patients with pacemakers and defibrillators continues to expand and JACC's leadership in this important technologic development was highlighted by the publication of an original study testing the efficacy of precautions devised to assure safety and quality of MRI studies in patients with cardiac devices (158), discussed in detail by an accompanying editorial by Roguin (159), one of the pioneers in this field. Indeed, 2009 was a bright year for MR investigators, patients, and cardiologists, as documented by the reports, editorial comments, and reviews published on this topic by JACC.

Although maturing quickly, the clinical role of CMR in daily practice remains uncertain. To answer this question, Bruder et al. (160) analyzed the results of a very large multicenter EuroCMR (European Registry) involving 11,040 consecutive patients. They reported the indications for performing this study and the complication rates that were involved. Of significance, they indicated that clinical management was impacted in two-thirds of patients; and in 16% of the cases, the final diagnosis based on CMR was different from that prior to study. These data provide strong evidence for the fact, that at least in these European centers, CMR has achieved an important role in the daily clinical practice of cardiology.

CMR is achieving an increasing role in the clinical investigation. In this regard, Tang et al. (161) employed CMR imaging using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid MRI to compare the effects of 10 versus 80 mg of atorvastatin on carotid plaque inflammation. Forty-seven patients with carotid stenosis of greater than 40% who demonstrated intraplaque accumulation of USPIO on MRI were randomized to either 10 or 80 mg of atorvastatin for 12 weeks. The 80-mg atorvastatin group manifested a significant reduction from baseline in inflammation by USPIO at 6 and at 12 weeks. Thus, these data demonstrate that MRI can be used to assess the pharmacologic efficacy of treatment with regard to pathophysiological phenomena such as inflammation. In an accompanying editorial, Fayad et al. (162) point out that there are many technical considerations to obtaining high-quality USPIO images, and that lymphatic uptake may interfere with interpretation. However, these editorialist agree that the existing data provide a stimulus for further investigation in this area.

	Valvular Heart Disease

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A novel concept to evaluate aortic stenosis severity is the valvuloarterial impedance; the prognostic value of this index was assessed in 544 asymptomatic patients with moderate-to-severe aortic stenosis (107). Patients with an index 4.5 mm Hg·ml^–1·m² had a 2.76-fold increased mortality risk after adjustment for other risk factors and treatment (surgery or medical). This new index may potentially further aid in risk stratification of asymptomatic patients with moderate-to-severe aortic stenosis (163).

Hemodynamic performance of percutaneous and surgical aortic valve bioprostheses was compared in 150 patients who underwent surgical or percutaneous valve replacement for severe aortic stenosis (164). Echocardiography demonstrated a significantly lower transprosthetic gradient in the patients with percutaneous valve replacement as compared with the surgical patients. Conversely, post-procedural aortic regurgitation was encountered more often in the patients with percutaneous valve replacement. Long-term outcome data are needed to further compare surgery with percutaneous valve replacement.

The entity of low-gradient severe aortic stenosis in the setting of normal LV function due to reduced LV stroke volume has recently drawn considerable attention. Believing that valvuloarterial impedance may play a role in this process, Hachicha et al. (108) determined to study the prognostic value of valvuloarterial impedance in asymptomatic aortic stenosis since it is a superior index of global hemodynamic load faced by the LV. They retrospectively analyzed the data in 554 consecutive patients having at least moderate aortic stenosis without symptoms. The 4-year survival was significantly lower in patients with a baseline valvuloarterial impedance greater than and equal to 4.5, and mortality was increased by 2.76-fold in such patients. Thus, increased valvuloarterial impedance clearly represents an excessive LV hemodynamic load and can be used to predict patients who are asymptomatic with significant stenosis in whom a poor outcome is likely.

The management of patients with low-flow/low-gradient aortic stenosis without contractile reserve continues to be problematic. Tribouilloy et al. (165) retrospectively analyzed the data in 81 such patients who were either referred for surgery or treated medically. In 42 propensity-matched patients, 5-year survival was markedly by aortic valve replacement (65% vs. 11%, p < 0.01). Associated bypass surgery and a maximal gradient of less than 20 mm Hg were independently predictive of operative mortality. Thus, these data would suggest that, despite a formidable operative mortality, patients with low-flow/low-gradient aortic stenosis are best served with surgery if at all possible.

An alternative to operative aortic valve replacement is percutaneous aortic valve replacement. In a state-of-the-art paper, Zajarias and Cribier (27) reviewed the state of percutaneous aortic valve replacement. They point out that it is a field in rapid transition, but that the Edwards SAPIEN and CoreValve devices are being used and evaluated in many patients throughout the world. They indicate that mid-term follow-up studies are very encouraging with regard to the absence of restenosis or prosthetic dysfunction.

The role of the endothelium of the aortic valve cusps themselves in the genesis of aortic valve disease is just now receiving attention. In a novel study, El-Hamamsy et al. (166) studied the mechanical properties of porcine aortic valve leaflets subjected to compounds capable of altering leaflet stiffness. They observed that serotonin induced a decrease in leaflet stiffness which was reversed by L-NAME or endothelial denudation, whereas endothelin-1 caused an increase in stiffness. These data clearly established the ability of the endothelium to regulate the mechanical properties of aortic valve leaflets, and point to a possible role in the genesis of aortic valve disease. In an accompanying editorial, Simmons (167) points out that valve mechanics have largely been viewed as an engineering issue in the past, but that there is an increasing appreciation for valve biology which may play an important role both in physiology and disease. The percutaneous treatment of mitral valve disease is also being pursued. Feldman et al. (168) reported the most recent findings in the EVEREST (Endovascular Valve Edge-to-Edge REpair Study) in which mitral valve repair is achieved with a mitral valve clip system. They reported on 107 patients followed for at least 12 months and indicated that 66% of the 76 successfully treated patients were free from death, mitral valve surgery, or mitral regurgitation of >2+ severity. These results early in the learning curve of the use of this device are considered encouraging, and further studies are continuing.

	Pre-Clinical Research

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Adenosine may decrease infarct size after ischemia-reperfusion, but its utility as a cardioprotective agent is limited by a short half-life and systemic side effects of hypotension and bradycardia. Takahama et al. (169) postulated that liposomes, which have been used in chemotherapy, may be used to deliver adenosine to ischemic myocardium, where vascular permeability is increased due to endothelial damage. Encapsulating liposomes with polyethylene glycol (PEG) can prolong the residence time and delay the degradation of adenosine. A 10-min intravenous infusion of PEGylated liposomal adenosine to rats with LAD occlusion, started 5 min prior to reperfusion, resulted in liposome accumulation in the border and infarct zones without hypotension or slower heart rates. There was a dose-dependent decrease in infarct size at 3 and 72 h, which did not occur with empty PEGylated lyosomes or free adenosine. The cardioprotective effects PEGylated liposomal adenosine were blocked by nonspecific and specific adenosine receptor antagonists. Cohen and Downey (154) in an editorial comment note that exogenous adenosine has been used to salvage ischemic myocardium in both preclinical and clinical studies with mixed success. The limitations of adenosine could be overcome by using PEGylated liposomes for drug delivery and targeting vehicle, which can be conveniently administered by an intravenous route without significant toxicity. This and other studies confirm that cardioprotective effects are inhibited by adenosine receptor antagonists.

Novel cardioprotective compounds in pre-clinical ischemia-reperfusion.   Glucagon-like peptide (GLP)-1 is a gut incretin hormone with insulinotropic and insulinomimetic properties that is cardioprotective in ischemia-reperfusion, but has a short half-life that requires continuous infusion. Timmers et al. (170) postulated that exenatide, a long-lasting GLP-1 analog, may be a useful alternative. This interesting compound derived from the saliva of venomous lizard gila monster, is a Food and Drug Administration–approved drug (Byetta from Amylin and Lilly) used to treat type 2 diabetes mellitus. In pigs with 75 min of left circumflex coronary artery occlusion, exenatide given prior to reperfusion and then injected subcutaneously twice daily decreased infarct size by 40% after 3 days. Exenatide increased insulin levels without inducing hypoglycemia, activated protective pAkt signaling, decreased apoptosis and oxidative stress, and improved systolic and diastolic LV function. Webb et al. (171) in an editorial comment note this is a highly translational study in a clinically applicable large animal model that adds support to the use of incretin analogs, since GLP-1 has been cardioprotective in preclinical and clinical studies. It is unclear whether the mechanisms of cardioprotection are related to exenatide and/or increase in insulin, or if the decrease in apoptosis and oxidative stress contribute to the beneficial effects.

Novel targets for attenuating LV remodeling after MI: pre-clinical study.   Buss et al. (172) tested the hypothesis that adverse LV remodeling after MI may be inhibited by targeting the mammalian target of rapamycin (mTOR) pathway. This pathway is involved in ventricular hypertrophy and remodeling and is clinically relevant, as mTOR inhibitors are used for immunosuppression in transplant patients and to prevent proliferation in drug-eluting stents. Everolimus, an inhibitor of mTOR, was given orally to rats 1 or 3 days after ligation of the LAD. Early treatment decreased infarct size, improved LV function and reduced remodeling 28 days after the MI. This was associated with increased autophagy (mTOR is a major regulator of this unique form of cell death), decreased NF-kappa B activity in the border zone, decreased macrophage invasion, and inflammation. The improvement in LV function was sustained for 3 months, even when everolimus was stopped after the first month. Delayed everolimus treatment initiated 3 days after MI did not alter infarct size, but still significantly improved LV remodeling and LV function. These results demonstrate the feasibility of targeting mTOR to improve LV remodeling with a clinically available mTOR inhibitor.

Novel methods to improve LV remodeling after MI: pre-clinical study.   Biomaterials injected into the heart have restraining effects that limit LV remodeling after MI. Leor et al. (173) tested the feasibility and safety of intracoronary injection of a calcium cross-linked alginate solution 4 days after anterior wall infarction in pigs. This compound is nonthrombogenic and forms a hydrogel scaffold in the infarcted region, which gradually dissolves and is replaced by myofibroblasts and collagen after 60 days. Injecting the alginate hydrogel did not cause significant arrhythmias, increase in troponin, inflammation, or fibrosis. There was a dose-dependent decrease in the extent of LV dilation, improved LV function, and 50% increase in scar thickness. The feasibility, safety, and effectiveness of this biomaterial to improve LV remodeling in a large animal model moves this novel approach a step closer towards clinical translation.

The role of monocytes in patients with AMI.   Monocytes play an important role in ischemic heart disease, but do not represent a homogeneous population of cells. Tsujioka et al. (174) used flow cytometry to identify 2 distinct subsets of circulating monocytes based on the expression of CD14 and CD16 in 36 patients undergoing primary PCI for STEMI. Circulating monocytes identified as CD14+CD16– increased with a peak at 3 days, whereas CD14+CD16+ monocytes peaked 5 days after MI. Peak levels of CD14+CD16–, but not of CD14+CD16+ monocytes were negatively associated with the extent of myocardial salvage 7 days after MI, as assessed by CMR, and were inversely associated with the extent of recovery in LV function (change in EF) 6 months following MI. Manipulating monocyte subsets that affect myocardial salvage may be a novel therapeutic target for patients with AMI.

Shantsila and Lip (175) make editorial comments on the diversity of monocytes and their functional role. CD14+CD16– monocytes produce inflammatory cytokines, reactive oxygen species and proteolytic enzymes and play an important phagocytic role to digest necrotic tissue in MI. This may be related to increased expression of monocyte chemoattractive protein (MCP)-1, which attracts monocytes and contributes to angiogenesis in the early phase of an AMI. In contrast, CD14+CD16+ monocytes are mobilized with exercise and correlate with atherogenic lipids, but were not associated with outcomes and have an unclear role in AMI.

The role of monocytes generated significant interest from Kavsak and Jaffe (176), who did not find a temporal increase in MCP-1 within 12 h in 216 patients with ACS. Shantsila and Lip (177) reply the time in their study (3 to 12 h) may be too early to observe an increase in monocytes that peaks after 48 to 72 h, and other large clinical ACS studies have found an increase in MCP-1 with prognostic significance. Imanashi et al. (178) concur it will be important to study more diverse groups, including patients with non-STEMI, to determine whether measuring monocyte subsets help to evaluate the optimal timing for interventions in ACS.

Glycemic control in patients with AMI.   The role of hyperglycemia was examined in 88 patients with a first AMI admitted for surgical coronary revascularization (179). Patients with hyperglycemia (glucose >140 mg/dl) were randomized to receive insulin to achieve intensive (lower glucose to 80 to 140 mg/dl), or conventional (maintain glucose at 180 to 200 mg/dl) glycemic control for 3 days prior to surgery. Patients with hyperglycemia had worse LV function than the 38 patients with normoglycemia (glucose <140 mg/dl), but it was better in patients with intensive than with conventional glycemic control. Biopsies of the peri-infarct area showed greater nitrotyrosine, iNOS, O₂-production, macrophages, T-lymphocytes, TNF-alpha, and caspase-3 levels in hyperglycemic patients, which was attenuated with intensive compared with conventional glycemic control. Thus, tight glycemic control reduces oxidative stress, inflammation, apoptosis, and improves LV function in AMI. Dandona et al. (180) in an editorial comment note these results are important in the context of several large clinical trials evaluating glucose and insulin in AMI. Although glucose-insulin-potassium solutions failed to improve outcomes in a large prospective randomized trial (CREATE–ECLA [Clinical Trial of Reviparin and metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation–Estudios Clinicos Latino America]), that trial demonstrated an adverse effect of hyperglycemia on mortality. Several studies have shown that insulin has anti-inflammatory and profibrinolytic independently of its effects on glucose, which may be cardioprotective. The present study by Marfella et al. (179) shows the beneficial effects of insulin on cardiac function with AMI that correlate with histological changes in inflammation and apoptosis in the human myocardium.

Targeting the cardiac ryanodine receptor to decrease diastolic calcium leak in experimental heart failure.   Calcium may leak from the sarcoplasmic reticulum (SR) with abnormalities in the skeletal muscle ryanodine receptor (RyR1) to cause malignant hyperthermia, and in cardiac ryanodine receptors (RyR2) to predispose to malignant arrhythmias. On the basis of similar positions of mutations in RyR1 and RyR2, Kobayashi et al. (181) found that dantrolene, a drug that binds to RyR1 to treat malignant hyperthermia, also binds and stabilizes cardiac RyR2. Dantrolene corrected defects in interdomain interactions of RyR2 in isolated cardiomyocytes from dogs with pacing-induced heart failure to decrease diastolic SR calcium leaks, decrease delayed afterdepolarizations, and improve cell shortening and calcium transients. Stabilization of RyR2 with dantrolene is a novel approach to treat heart failure. Shannon and Lew (182) in an editorial comment note several interrelated mechanisms may contribute to abnormal SR calcium leak, including increased phosphorylation of RyR2, enhanced sensitivity to luminal SR calcium, and weakened interdomain interactions of RyR2. The current study demonstrated that this last mechanism occurs in heart failure, and can be treated with dantrolene to decrease SR calcium leak. It is unknown if the benefits are limited to mutations at dantrolene binding sites, which cause arrhythmias and sudden death in some cases of catecholaminergic polymorphic VT and atypical RV cardiomyopathy. If dantrolene has broader effects to decrease SR calcium leak, it may be a useful adjunct to treat heart failure. Dantrolene has been used for decades to treat acute malignant hypothermia and chronic muscle spasticity after spinal cord injuries and strokes, but may be require higher doses to stabilize RyR2 in heart disease.

Alpha-1-adrenergic receptor (AR) subtypes in human coronary arteries.   Jensen et al. (183) examined the distribution and subtypes of alpha-1- and -2-ARs in human epicardial coronary arteries from 19 transplant recipients and 6 unused donors. There are scant data on the distribution and function of alpha-1-AR and -2-AR in humans, which play important regulatory roles in coronary vasomotor tone and blood flow. The alpha-1-AR mediate constriction of large epicardial coronary arteries and arterioles, whereas alpha-2-AR act on the coronary microcirculation. Of the 3 molecular subtypes of alpha-1-AR, messenger ribonucleic acid (mRNA) expression and protein were the most abundant for the alpha-1D subtype in the coronary arteries, whereas alpha-1A and -1B subtypes played only a minor role. There was alpha-1D–induced activation of extracellular signal-regulated kinase in coronary smooth muscle cells with low levels of norepinephrine, indicating the function significance of these receptors. This is consistent with the high affinity of alpha-1D-AR for norepinephrine, which causes constriction at low doses. These results have clinical implications with the widespread use of nonselective alpha-AR inhibitors (e.g., to treat prostate hypertrophy) and emergence of selective alpha-AR antagonists.

Braun and Insel (184) note the importance of human data in an editorial comment aptly titled "The Best ‘Model System' for Human (Coronary Arteries) Is Human." Much of the knowledge of adrenergic receptors is based on preclinical studies and in vitro studies, and there are significant species differences. It is crucial to obtain human data as the best "model system" to understand the role and regulation of alpha-AR in human coronary arteries.

	Biomarkers

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Although troponin assays have markedly improved the diagnosis of MI, the time lag between presentation and the rise in troponin levels leads to possible delays in diagnosis. Reichlin et al. (185), in a study of 487 consecutive patients presenting to the emergency department with possible MI, examined the incremental value of a novel marker of copeptin, the C-terminal part of the vasopressin prohormone. They found that the combination of troponin T and copeptin measured at presentation improved the diagnosis of MI, with an area under the receiver-operating characteristic curve of 0.97, compared with 0.86 for troponin T alone (p < 0.001).

Surveillance of with timing of surgery in mitral regurgitation patients remains challenging. Pizarro et al. (186) demonstrated in prospective fashion that in patients with severe asymptomatic mitral regurgitation with normal ejection fractions, a cut point of B-type natriuretic peptide (BNP) at 105 pg/ml could discriminate a subgroup of patients at higher risk of unsatisfactory outcome after surgery. In an accompanying editorial, McCullough and Hanzel (187) suggest that a change in BNP is probably the first clinical signal, prior to symptoms or echo alterations, that will herald near-term higher risk.

Although natriuretic peptide (NP) testing has shown great value in diagnosing heart failure in adults, it has not been well studied in the neonate and pediatric population. Law et al. (188) studied subjects in the acute care setting who had possible heart failure. A BNP of 170 pg/ml yielded a sensitivity of 94% and a specificity of 73% in the neonatal group, and 87% and 70% in the older group using a BNP of 41 pg/ml. In the accompanying editorial, Socrates et al. (189) felt that BNP testing may have a great future as a possible tool in adding details to the picture of the pediatric heart failure patient.

The role of NPs in surgical patients are not well established. To this end, Karthikeyan et al. (190) found clear evidence for the association between pre-operative elevated levels of NPs and post-operative occurrence of MACE in noncardiac surgery patients. In an accompanying editorial, Bolliger et al. (191) believe that future studies will be needed to fully evaluate whether specific NP-based treatment modifications will result in improved outcomes of surgical patients.

It has not been well known that NPs are lipolytic and slow gastric emptying and absorption. Adiponectin, a 244–amino acid peptide is also emerging as an important regulator of metabolism. Tsukamoto et al. (192) demonstrated that both atrial natriuretic peptide (ANP) and BNP, via the cyclic GMP pathway, increase adiponectin mRNA expression and increase adiponectin secretion from cultured adipocytes. The authors have speculated that in the setting of heart failure, adiponectin secretion may occur so as to attenuate the chronic energy deprivation the heart faces as it switches from predominantly fatty acid oxidation to glucose oxidation. Also, the NP-induced lipolysis and adiponectin secretion could aid in weight loss, a potential unloading situation for the heart.

NPs have also been utilized as a surrogate for clinical congestion in patients hospitalized for acute heart failure. Cohen-Solal et al. (193), in a retrospective analysis of the SURVIVE (SURVival of patients with acute heart failure in need of Intra-VEnous inotropic support) trial, demonstrated that patients admitted with heart failure who had decreases in BNP >30% over 5 days of hospitalization had a 31-day risk reduction of all-cause mortality of 67% and a 180-day risk reduction of 47%. The results demonstrate that early lowering of BNP predicts both short- and long-term mortality risks; this suggests that BNP reduction may serve as a suitable prognostic marker of all-cause mortality.

McKie et al. (194) reported the biological properties of a mutant ANP identified in association with a familial form of atrial fibrillation. This mutant form activates cGMP in vitro and exerts greater and more sustained natriuretic, diuretic, glomerular filtration rate, and renal blood flow than native ANP. In an accompanying editorial, de Bold (195) points out that studies such as this suggest strategies to improve upon the biological potency or the half-life of the hormone for therapeutic purposes in cardiorenal disease.

Although troponin levels have been used to estimate prognosis in heart failure, most studies involving hospitalized patients have used single measurements. Miller et al. (196) studied 172 ambulatory New York Heart Association functional class III to VI patients with serial cardiac troponin T (cTnT) measurements every 3 months over a 2-year period. The primary end point was death or cardiac transplantation. Elevations of cTnT levels, using a threshold of 0.01 ng/ml, in ambulatory HF patients was associated with increased risk of events, especially if the cTnT elevations were persistently >0.01 ng/ml. Thus, this study suggests that serial measurements of troponin in ambulatory HF patients may add to risk assessment.

Venge et al. (197) was one of the first to evaluate the analytical and clinical performance of a new sensitive troponin I assay (Beckman Coulter). They found the 99th percentile cutoff of 0.01 µg/l. Using this assay, they found a sensitivity of 85% and a specificity of 90% in discriminating healthy subjects from those with ACS. In an accompanying editorial, Hollander (198) points out that although the increased sensitivity will help rule in more patients in quicker fashion, these lower cut points are likely to decrease specificity, possibly contributing to overcrowding of intensive care unit and telemetry beds.

There have been little data regarding relative prognostic value during the time course of ACS. Eggers et al. (199) measured a panel of biomarkers at randomization, 6 weeks, and 6 months for 5-year outcomes of death and MI. Paradoxical to some earlier data, only NT-proBNP level at 6 weeks added significant prognostic information to statistical models containing conventional risk indicators.

	Genomics/Genetics

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McDermott and Lloyd-Jones (200) provide a current and clinically relevant update of the role of biomarkers and genetics in PAD. The effects of statin therapy on elevated C-reactive protein and all-cause mortality in patients with PAD suggest that the protective effect of statins is primarily in individuals with high C-reactive protein levels. Understanding the fraction of PAD that is heritable is important for assessing the risk of family members developing PAD and building in prevention strategies early in clinical care. McDermott and Lloyd-Jones (200) estimate the genetic heritability of PAD to be between 22% and 48% after adjusting for cardiovascular risk factors. The number of genetic markers discovered for PAD have lagged behind those for stroke and other complex cardiovascular diseases. Two loci are reviewed that have met genome-wide significance, one on chromosome 1p and the other on chromosome 15q24 (200,201). Replication in additional cohorts and testing with additional intermediate phenotypes are next steps. The region on chromosome 15q24 is intriguing, as it contains a cluster of nicotinic acetylcholine receptors, mutations that are associated with increased risk of PAD in smokers, as well as smoking quantity, nicotine dependence, and lung cancer (202).

Two articles were published in which unique mutations in 1 gene were associated with both hypertrophic cardiomyopathy and dilated cardiomyopathy (203,204). This gene is cardiac ankyrin repeat domain 1 (ANKRD1). Arimura et al. (203) identified 3 missense mutations in ANKRD1 in 3 unrelated individuals with hypertrophic cardiomyopathy. Moulik et al. (204) demonstrated that a distinct set of mutations in ANKRD1 were associated with dilated cardiomyopathy. Testing for cosegregation of these individual mutations with disease in family members in additional populations will be helpful for further clarifying the role of ANKDR1 in heart disease and development. Unique mutations in the same gene leading to different phenotypes is referred to as "phenotypic heterogeneity." Past examples and a lengthier description of phenotypic heterogeneity is described in an editorial by Mestroni et al. (205) that accompanied the back-to-back papers on ANKRD1 in JACC. The ability to identify distinct mutations in a single gene associated with multiple clinical phenotypes is likely to increase as technology continues to improve.

It is estimated that nearly 30% of children exhibit cardiac dysfunction within 10 years after cardiac transplantation, accounting for up to 20% of deaths (206). Auerbach et al. (206) reported that mutations in the renin-angiotensin-aldosterone system (RAAS) in a transplant recipient are associated with higher risks of rejection, graft cytokine expression, graft dysfunction, and higher mortality in pediatric patients following cardiac transplantation. These findings suggest that in the setting of pediatric cardiac transplantation, genotype can be used to help risk stratify patients and potentially tailor clinical monitoring and treatment.

Finally, Margulies et al. (207) capture how genetics and genomics are providing new insight into mechanisms of heart failure. This review outlines key new terminology and highlights an update of disease-susceptibility genes for heart failure. A succinct discussion of epigenetics, alternative mRNA splicing, and microRNA is provided along with specific examples in the setting of heart failure. A number of recent articles have been written in the past year providing evidence for microRNAs in heart and vascular development and disease. Finally, this review by Margulies et al. (207) provides the clinician with an update of how genetics and genomics are currently being used diagnostically in the clinic.

Genetic variants have been shown to predict the likelihood only of rhabdomyolysis following administration of high-dose simvastatin (80 mg), but little is known about the effect of these variants on the toxicity of other statins, or on the more common problem of troublesome myalgias. Voora et al. (208) demonstrate that the reduced function SLCO1B1*5 allele is associated with adverse muscle side effects for 3 other statins, including the problem of muscle pain without frank rhabdomyolysis. These findings partially explain the basis for statin intolerance, a common clinical problem.

Wang et al. (209) describe a genetic variation associated with control of the circulation and development of hypertension. These findings demonstrate a novel pathophysiological link between the NPY1R locus and blood pressure, which may yield new approaches to understanding the mechanism and management of hypertension. Eventually, these findings may yield new drug targets for BP control.

	Congenital Heart Disease

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Momenah et al. (210) present extensions of pulmonary valve implantation techniques developed for patients with enlarged RV outflow tracts after patching. They studied 13 patients with a mean age of 14.3 years who had either truncus arteriosus repair of pulmonary atresia (PA), tetralogy repair, or other complex heart disease. They deployed stents in the RV outflow tract's narrowest diameter, which extended above and below that narrowed area. Stents were pre-mounted on a 22 x 40-mm balloon catheter and dilated in place, after which a double-balloon method was used for placement of the 22-mm Melody valve within the stent.

All of these patients had had residual obstruction as well as insufficiency, and relief of the obstructive component was evidenced by RV pressure dropping from 61 to 37 mm Hg, reduction in gradient from 39.6 to 12.2, a rise in pulmonary diastolic pressure, and significant reduction in the degree of pulmonary regurgitation to no more than a mild grade in any patient. The study suggests that pre-stenting allows pulmonary valve implantation, avoiding the need to redo surgical procedures in patients with tetralogy of Fallot repair and RV outflow patch. Further follow-up is, of course, required.

The collaborative study by Beca et al. (211) explored the issue of pre-operative brain injury in newborn infants, which may occur in utero or before their corrective surgery. The specific issue relates to previous studies reported by McQuillen et al. (212), which suggested that those infants who had a balloon atrial septostomy were more likely to have brain abnormalities, particularly white matter injury, not specifically ischemic stroke. This 2-center study included 64 infants (44 with transposition, 13 with hypoplastic left heart, and 7 with PA). Thirty-three of the babies had balloon atrial septostomy: 25 were transposition and intact ventricular septum, and 8 with a ventricular septal defect as well. Brain injury occurred as white matter injury with similar incidence in transposition of the great arteries (TGA), hypoplastic left heart syndrome, and PA: 27%, 23%, and 29%, respectively. Stroke occurred in 3 infants, 3% of those with balloon atrial septostomy, 9% of those who did not have balloon atrial septostomy. There were 4 important findings in the study. Brain injury was present in 30% of the patients; there was a similar rate in the lesions; the pattern was characteristically white matter injury; and there was no association between balloon atrial septostomy and brain injury in patients with TGA. An important editorial comment by Mosca (213) points out that the present study refutes the findings of McQuillen et al. (212). The Beca et al. (211) study shows predominantly white matter injury, with strokes being uncommon, and no association of injury related specifically to balloon atrial septostomy. Unfortunately, neither study performed MRI scans before the balloon septostomy.

Another paper in Circulation by Petit et al. (214) from the Children's Hospital of Philadelphia had the same findings that both the degree of oxygenation and the time to surgery were major determinants of brain injury and must be held in perspective. Also, Cheng (215) again pointed out a 10% incidence of perioperative stroke—a different type of abnormality—half of which were present pre-operatively and point to the need for asking questions: whether fetal diagnosis and maternal care might impact birth weight and mitigate this risk.

Two papers on aortopathy in congenital heart disease patients and an editorial comment appeared this year in JACC. The paper by Biner et al. (216) examined the prevalence of aortic dilation and abnormal elastic properties in first degree relatives of patients with bicuspid aortic valve. This relationship to genetic determinants is also examined in an invited editorial comment by Silberbach (217). The study reports that 32% of bicuspid aortic valve patients who did not have aortic valve abnormalities had abnormal aortic root, annulus, and sinus dimensions significantly larger than the controls, and found that elastic aortic root properties including distensibility and stiffness index are also present in the first-degree relatives.

Similar studies by Loscalzo et al. (218) reported aortic abnormalities and aortic dilation in 35% families of patients with coronary aortic dissections or rupture, suggesting that these are independent manifestations of a genetic disorder. Biner and colleagues admit to the limitation that the first-degree relatives were identified from patients at referral centers who had advanced valvular and aortic disease, since these relatives were more willing to be studied.

In a paper invited before the 2 papers just discussed and published the week before, Yetman and Graham (219) discuss the dilated aorta in patients with congenital heart disease, adding insights of some of the febrilin abnormalities in Marfan aortopathies, the role of proteolytic enzymes and tissue inhibitors of metalloproteinases as well as TGF-beta, a superfamily of cytokines that is important for maintenance of vascular health on embryogenesis.They point out that the spectrum of aortic impairment not only extends to families with bicuspid aortic valves, but has been found with greater prevalence in patients with Turner's syndrome. The propensity for similar changes and risk of aortic rupture exists in patients with coarctation and the abnormal aortic dilation and abnormalities of aortic physiology both in tetralogy of Fallot patients and those with dextro-TGA involving dilation of the neo-aortic. They also point out that aortic and pulmonary dissection have occurred in unrepaired truncus arteriosus, aorticopulmonary window, and ductus arteriosus. The large cohort with congenital heart disease and aortic pathology surviving to adulthood will make this a major area in which multicenter trials of medical therapies to prevent progressive aortic pathology in patients with CHD-related aortopathy.

An important multicenter study on pediatric nonpost-operative junctional ectopic tachycardia (JET), medical management, and interventional therapies was presented by Collins et al. (220). Ninety-four patients with JET and 5 patients with accelerated junctional rhythm, with a mean age of 0.8 years (range fetus to 16 years) were identified. Those presenting at <6 months of age were likely to have faster JET rates and incessant JET. These are truly sick youngsters who presented with either fetal tachycardia with or without hydrops, heart failure, rapid regular rates, and syncope. Presentation was more likely to be incessant in those <6 months of age. Median JET was 209 beats/min, with rates as high as 320 beats/min, tending to be higher in the younger patients. Successful treatment was most common with amiodarone. Additional treatment strategies included radiofrequency ablation or cryoablation in 17 and 27 patients, respectively, with success rates of 82% and 85%, and pacemaker implant in 14%. The 4 deaths all occurred in patients <6 months old. Comorbidities included prematurity, possible myocarditis, the need for extracorporeal membrane oxygenation (ECMO), and short gut syndrome from arrest bowel ischemia. This international multicenter study documents outcomes of patients with a difficult-to-treat abnormality, especially dangerous and difficult in smaller patients, and shows improved outcomes with a combination of currently available.

An important international study by Spazzolini et al. (221) reported on the severe clinical manifestations of LQTS in infants. A worrisome and important subpopulation of infants was identified: 20 who died suddenly and 16 who had an acute cardiac event, 34 who experience syncope, as well as a group of 3,253 who were asymptomatic. Forty percent of the patients were female, all of whom had a corrected QT (QTc) interval of >500 ms. Four of the 20 infants with sudden cardiac death had had a prior event, 4 of them were receiving beta-blockers. While small, this is a very high-risk group. In a helpful and important editorial comment, Triedman (222) points out that the long QT genotypes in infants might differ substantially from those observed in older patients. He also points out that screening had potentially diluted the phenotypic severity, since a wider population base would show patients with milder forms of long QT interval as now fallen into our understanding of the population. For the sickest patients, the administration of beta-blockade was not associated with a survival benefit. However, as the population becomes diluted, evidence for beta-blocker efficacy will continue to be acquired in patients with the milder spectrum of the disease. Currently, it is cost prohibitive to routinely genotype newborns, but it is advisable to genotype infants in long QT families and newborns found to have clear QT prolongation.

Opotowsky et al. (223) performed hospital national inpatient sampling to identify adults over 18 years of age admitted with diagnostic codes related to congenital heart disease. The number of hospitalizations from 1998 to 2005 doubled, including both simple and complex forms of heart disease. The complex heart disease category increased by 60%, and total charges related to adult congenital heart services increased by 127% compared with national total hospital charges of only 66%. Thus, care for adult congenital heart disease is claiming an increasing proportion of hospital resources and health care providers in all specialties will likely encounter these complex patients with increased frequency—emphasizing the need for cardiologists with specialized adult CHD training to care for this burgeoning population.

	JACC White Papers

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A new format introduced into JACC this year is "JACC White Papers." Short consensus statements by experts regarding commonly encountered clinical issues for which no definitive evidence existed from research studies. These White Papers are not guidelines comparable to those issued by the ACC or AHA, but are meant to provide some useful context for dealing with these issues, given the existing data.

The first White Paper published in JACC dealt with the application of CMR in patients with known or suspected myocarditis (224). Friedrich et al. (224) discuss the multiple diagnostic approaches to myocarditis and their limitations, and then review the published data regarding the application of magnetic resonance in this disorder including the detection of functional abnormalities, pericardial effusion, morphologic abnormalities, tissue characterization, and necrosis or fibrosis. They propose a comprehensive use of a magnetic resonance criteria to both diagnose and follow patients with myocarditis.

A challenging problem often encountered clinically is the patient requiring triple anticoagulant therapy including aspirin, clopidogrel, and warfarin. Such patients typically require intracardiac stents in the setting of AF or prosthetic valves, etc. In the absence of definitive data from the randomized clinical trials, Holmes and colleagues address the existing data and how they might be applied to current decision-making (225). The document prepared by the writing group recognizes the increased bleeding risk inherent in the use of triple anticoagulant therapy, and that this risk increases with time. Therefore, they advocate the consideration of measures such as the use of their metal stents to minimize the duration that triple anticoagulant therapy would be required. For those patients in whom triple therapy is clearly felt to be best, they recommend lose-dose (<100 mg) aspirin, conventional dose (75-mg clopidogrel) and an international normalized ratio (INR) target close to 2.0.

Another common clinical dilemma encountered by physicians is the management of a patient receiving dual antiplatelet therapy in whom endoscopic gastrointestinal procedures are to be undertaken. Such patients will nearly always have a very well-established reason for the dual antiplatelet therapy, and it is clear that the sudden cessation of such therapy, particularly in the first 6 months after procedure, can present a significant risk of acute ST in patients who have received these devices. Although the cardiovascular complications of endoscopic procedures are very infrequent, bleeding is a significant consideration. In a JACC White Paper, Becker et al. (226) review all the data that currently exist that can be brought to bear on decisions in this setting. They recommend that all elective endoscopic procedures be deferred for up to 12 months following PCI and DES placement. For those gastrointestinal procedures that must be undertaken, and which impose significant bleeding risk, it is recommended that the thienopyridine be discontinued 5 to 7 days before the gastrointestinal procedure, that aspirin be continued, and that the patient be restored as soon as possible.

	References

Top Interventional Cardiology Heart Failure Electrophysiology Echocardiography CT and Nuclear Imaging MRI Valvular Heart Disease Pre-Clinical Research Biomarkers Genomics/Genetics Congenital Heart Disease JACC White Papers References

 
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176. Kavsak PA, Jaffe AS. Peripheral blood monocyte subset assessment in non–ST-elevation myocardial infarction is required(letter) J Am Coll Cardiol 2010;55:169.[Free Full Text]

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