Featured Journal Club to Go

Alawi A. Alsheikh-Ali, MD, Prasad V. Maddukuri, MD, Hui Han, MD, Richard H. Karas, MD, PHD

OBJECTIVES
We sought to assess the relationship between the magnitude of low-density lipoprotein cholesterol (LDL-C) lowering and rates of elevated liver enzymes, rhabdomyolysis, and cancer.

BACKGROUND
Although it is often assumed that statin-associated adverse events are proportional to LDL-C reduction, that assumption has not been validated.

METHODS
Adverse events reported in large prospective randomized statin trials were evaluated. The relationship between LDL-C reduction and rates of elevated liver enzymes, rhabdomyolysis, and cancer per 100,000 person-years was assessed using weighted univariate regression.

RESULTS
In 23 statin treatment arms with 309,506 person-years of follow-up, there was no significant relationship between percent LDL-C lowering and rates of elevated liver enzymes (R2 less than 0.001, p = 0.91) or rhabdomyolysis (R2 = 0.05, p = 0.16). Similar results were obtained when absolute LDL-C reduction or achieved LDL-C levels were considered. In contrast, for any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels (R2 = 0.43, p = 0.009), whereas no such association was demonstrated with percent LDL-C reduction (R2 = 0.09, p = 0.92) or absolute LDL-C reduction (R2 = 0.05, p = 0.23).

CONCLUSIONS
Risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. However, the risk of cancer is significantly associated with lower achieved LDL-C levels. These findings suggest that drug- and dose-specific effects are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer. (J Am Coll Cardiol 2007;50:409-18) (c) 2007 by the American College of Cardiology Foundation

Jacqueline Saw, MD, Danielle M. Brennan, MS, Steven R. Steinhubl, MD, Deepak L. Bhatt, MD, Koon-Hou Mak, MD, Keith Fox, MB, CHB,. Eric J. Topol, MD, on behalf of the CHARISMA Investigators

OBJECTIVES
The purpose of this study was to evaluate the potential impact of clopidogrel and statin interaction in a randomized, placebo-controlled trial with long-term follow-up.

BACKGROUND
There are conflicting data regarding whether statins predominantly metabolized by CYP3A4 reduce the metabolism of clopidogrel to its active metabolite and diminish its clinical efficacy.

METHODS
The CHARISMA trial was a randomized trial comparing long-term 75 mg/day clopidogrel versus placebo in patients with cardiovascular disease or multiple risk factors on aspirin. The primary end point was a composite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months. We performed a secondary analysis evaluating the interaction of clopidogrel versus placebo with statin administration, categorizing baseline statin use to those predominantly CYP3A4 metabolized (atorvastatin, lovastatin, simvastatin; CYP3A4-MET) or others (pravastatin, fluvastatin; non–CYP3A4-MET).

RESULTS
Of 15,603 patients enrolled, 10,078 received a statin at baseline (8,245 CYP3A4-MET, 1,748 non-CYP3A4-MET) and 5,496 did not. For the overall population, the primary end point was 6.8% with clopidogrel and 7.3% with placebo (hazard ratio [HR] 0.93; p = 0.22). This was similar among patients on CYP3A4-MET (5.9% clopidogrel, 6.6% placebo, HR 0.89; p = 0.18) or non-CYP3A4-MET statin (5.7% clopidogrel, 7.2% placebo, HR 0.78; p = 0.19). There was no interaction between statin types and randomized treatment (p = 0.69). Patients on atorvastatin (n = 4,127) (5.7% clopidogrel, 7.1% placebo, HR 0.80; p = 0.06) or pravastatin (n = 1,440) (5.1% clopidogrel, 7.0% placebo, HR 0.72; p = 0.13) had similar event rates.

CONCLUSIONS
Despite theoretic concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration, there was no evidence of an interaction clinically in a large placebo-controlled trial with long-term follow-up. (J Am Coll Cardiol 2007;50:291-5) (c) 2007 by the American College of Cardiology Foundation

Piergiovanni Buonamici, MD, Rossella Marcucci, MD, Angela Migliorini, MD, Gian Franco Gensini, MD, Alberto Santini, MD, Rita Paniccia, MD, Guia Moschi, MD, Anna Maria Gori, MD, Rosanna Abbate, MD, David Antoniucci, MD

OBJECTIVES
We sought to determine whether nonresponsiveness to clopidogrel as revealed by high in vitro post-treatment platelet reactivity is predictive of drug-eluting stent (DES) thrombosis.

BACKGROUND
No data exist about the impact of nonresponsiveness to clopidogrel on the risk of DES thrombosis.

METHODS
We conducted a prospective observational cohort study from July 2005 to August 2006 in an academic hospital. A total of 804 patients who had successful sirolimus- or paclitaxel-eluting stent implantation were assessed for post-treatment platelet reactivity after a loading dose of 600 mg of clopidogrel. Patients with platelet aggregation by 10 mu mol adenosine 5'-diphosphate greater than or equal to 70% were defined as nonresponders. All patients received chronic dual antiplatelet treatment (aspirin 325 mg and clopidogrel 75 mg daily) for 6 months. The primary end point was the incidence of definite/probable early, subacute, and late stent thrombosis at 6-month follow-up.

RESULTS
The incidence of 6-month definite/probable stent thrombosis was 3.1%. All stent thromboses were subacute or late. Of 804 patients, 105 (13%) were not responsive to clopidogrel. The incidence of stent thrombosis was 8.6% in nonresponders and 2.3% in responders (p less than 0.001). By multivariate analysis, the predictors of stent thrombosis were as follows: nonresponsiveness to clopidogrel (hazard ratio [HR] 3.08, 95% confidence interval [CI] 1.32 to 7.16; p = 0.009), left ventricular ejection fraction (HR 0.95, 95% CI 0.92 to 0.98; p = 0.001), total stent length (HR 1.01, 95% CI 1.00 to 1.02; p = 0.010), and ST-segment elevation acute myocardial infarction (HR 2.41, 95% CI 1.04 to 5.63; p = 0.041).

CONCLUSIONS
Nonresponsiveness to clopidogrel is a strong independent predictor of stent thrombosis in patients receiving sirolimus- or paclitaxel-eluting stents. (J Am Coll Cardiol 2007;49:2312-7) (c) 2007 by the American College of Cardiology Foundation

C. Michael Gibson, MS, MD, FACC, Sabina A. Murphy, MPH, Gilles Montalescot, MD, David A. Morrow, MD, MPH, FACC, Diego Ardissino, MD, Marc Cohen, MD,. Dietrich C. Gulba, MD, Oscar H. Kracoff, MD, Basil S. Lewis, MD, FACC, Nathan Roguin, MD, Elliott M. Antman, MD, FACC, Eugene Braunwald, MD, MACC, for the ExTRACT-TIMI 25 Investigators

OBJECTIVES
We sought to evaluate whether enoxaparin (ENOX) is superior to unfractionated heparin (UFH) as adjunctive therapy for patients with ST-segment elevation myocardial infarction (STEMI) who receive fibrinolytic therapy and subsequently undergo percutaneous coronary intervention (PCI) by analyzing data from the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction 25) trial.

BACKGROUND
Limited data are available on the use of ENOX compared with UFH as adjunctive therapy in STEMI patients treated with fibrinolytic therapy and subsequent PCI.

METHODS
A total of 20,479 STEMI patients who received fibrinolytic therapy were randomized to a strategy of ENOX throughout index hospitalization or UFH for at least 48 h, with blinded study drug to continue if PCI was performed. The primary end point of death or recurrent MI through 30 days was compared for ENOX versus UFH among the patients who underwent subsequent PCI (n = 4,676).

RESULTS
The mean (plus or minus SD) of apnea-hypopnea index was significantly higher in patients with CSA (34 plus or minus 25/h) than those without CSA (2 plus or minus 1/h). Most of these events were central apneas. In Cox multiple regression analysis, 3 of 24 confounding variables independently correlated with survival. The median survival of patients with CSA was 45 months compared with 90 months of those without CSA (hazard ratio = 2.14, p = 0.02). The other 2 variables that correlated with poor survival were severity of right ventricular systolic dysfunction and low diastolic blood pressure.

CONCLUSIONS
In patients with systolic HF, CSA, severe right ventricular systolic dysfunction, and low diastolic blood pressure might have an adverse effect on survival. (J Am Coll Cardiol 2007;49:2028-34) (c) 2007 by the American College of Cardiology Foundation

Shahrokh Javaheri, MD, Rakesh Shukla, PHD, Haoyue Zeigler, MS, Laura Wexler, MD

OBJECTIVES
The purpose of this study was to determine whether central sleep apnea (CSA) contributes to mortality in patients with heart failure (HF).

BACKGROUND
Cheyne-Stokes breathing with CSA commonly occurs in patients with systolic HF. Consequences of CSA, including altered blood gases and neurohormonal activation, could result in further left ventricular dysfunction. Therefore, we hypothesized that CSA might contribute to mortality of patients with HF.

METHODS
We followed 88 patients with systolic HF (left ventricular ejection fraction lesser that or equal to 45%) with (n = 56) or without (n = 32) CSA. The median follow-up was 51 months.

RESULTS
The mean (plus or minus SD) of apnea-hypopnea index was significantly higher in patients with CSA (34 plus or minus 25/h) than those without CSA (2 plus or minus 1/h). Most of these events were central apneas. In Cox multiple regression analysis, 3 of 24 confounding variables independently correlated with survival. The median survival of patients with CSA was 45 months compared with 90 months of those without CSA (hazard ratio = 2.14, p = 0.02). The other 2 variables that correlated with poor survival were severity of right ventricular systolic dysfunction and low diastolic blood pressure.

CONCLUSIONS
In patients with systolic HF, CSA, severe right ventricular systolic dysfunction, and low diastolic blood pressure might have an adverse effect on survival. (J Am Coll Cardiol 2007;49:2028-34) (c) 2007 by the American College of Cardiology Foundation

Franco Giada, MD, Michele Gulizia, MD, Maura Francese, MD, Francesco Croci, MD,Lucio Santangelo, MD, Maurizio Santomauro, MD, Eraldo Occhetta, MD, Carlo Menozzi, MD, Antonio Raviele, MD

OBJECTIVES
The aim of the study was to compare the diagnostic yield and the costs of implantable loop recorder (ILR) with those of the conventional strategy in patients with unexplained palpitations.

BACKGROUND
In patients with unexplained palpitations, especially in those with infrequent symptoms, the conventional strategy, including short-term ambulatory electrocardiogram (ECG) monitoring and electrophysiological study, sometimes fails to establish a diagnosis.

METHODS
We studied 50 patients with infrequent (Lesser than or equal to 1 episode/month), sustained (Greater than 1 min) palpitations. Before enrollment, patients had a negative initial evaluation, including history, physical examination, and ECG. Patients were randomized either to conventional strategy (24-h Holter recording, a 4-week period of ambulatory ECG monitoring with an external recorder, and electrophysiological study) (n = 24) or to ILR implantation with 1-year monitoring (n = 26). Hospital costs of the 2 strategies were calculated.

RESULTS
A diagnosis was obtained in 5 patients in the conventional strategy group, and in 19 subjects in the ILR group (21% vs. 73%, p lesser than 0.001). Despite the higher initial cost, the cost per diagnosis in the ILR group was lower than in the conventional strategy group (Euro 3,056 plus or minus Euro 363 vs. Euro 6,768 plus or minus Euro 6,672, p = 0.012).

CONCLUSIONS
In subjects without severe heart disease and with infrequent palpitations, ILR is a safe and more cost-effective diagnostic approach than conventional strategy. (J Am Coll Cardiol 2007;49:1951-6) (c) 2007 by the American College of Cardiology Foundation

Matthew J. Budoff, MD, Leslee J. Shaw, PHD, Sandy T. Liu, Steven R. Weinstein, Tristen P. Mosler, Philip H. Tseng, Ferdinand R. Flores, Tracy Q. Callister, MD, Paolo Raggi, MD, Daniel S. Berman, MD

OBJECTIVES
The purpose of this study was to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography in asymptomatic patients for the prediction of all-cause mortality.

BACKGROUND
Several smaller studies have documented the efficacy of CAC testing for assessment of cardiovascular risk. Larger studies with longer follow-up will lend strength to the hypothesis that CAC testing will improve outcomes, cost-effectiveness, and safety of primary prevention efforts.

METHODS
We used an observational outcome study of a cohort of 25,253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk. Multivariable Cox proportional hazards models were developed to predict all-cause mortality. Risk-adjusted models incorporated traditional risk factors for coronary disease and CAC scores.

RESULTS
The frequency of CAC scores was 44%, 14%, 20%, 13%, 6%, and 4% for scores of 0, 1 to 10, 11 to 100, 101 to 400, 401 to 1,000, and greater than 1,000, respectively. During a mean follow-up of 6.8 plus or minus 3 years, the death rate was 2% (510 deaths). The CAC was an independent predictor of mortality in a multivariable model controlling for age, gender, ethnicity, and cardiac risk factors (model chi-square equal 2,017, p less than 0.0001). The addition of CAC to traditional risk factors increased the concordance index significantly (0.61 for risk factors vs. 0.81 for the CAC score, p less than 0.0001). Risk-adjusted relative risk ratios for CAC were 2.2-, 4.5-, 6.4-, 9.2-, 10.4-, and 12.5-fold for scores of 11 to 100, 101 to 299, 300 to 399, 400 to 699, 700 to 999, and greater than 1,000, respectively (p less than 0.0001), when compared with a score of 0. Ten-year survival (after adjustment for risk factors, including age) was 99.4% for a CAC score of 0 and worsened to 87.8% for a score of greater than 1,000 (p less than 0.0001).

CONCLUSIONS
This large observational data series shows that CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality. (J Am Coll Cardiol 2007;49:1860-70) (c) 2007 by the American College of Cardiology Foundation

Hanqiao Wang, MD, John D. Parker, MD, FACC, Gary E. Newton, MD, FACC, John S. Floras, MD, DPHIL, FACC, Susanna Mak, MD, PHD, Kuo-Liang Chiu, MD, MSC, Pimon Ruttanaumpawan, MD, George Tomlinson, PHD, T. Douglas Bradley, MD

J Am Coll Cardiol 2007;49:1625–31

OBJECTIVES
This study sought to determine, in patients with heart failure (HF), whether untreated moderate to severe obstructive sleep apnea (OSA) is associated with a higher mortality rate than in patients with mild to no sleep apnea (M-NSA).

BACKGROUND
Obstructive sleep apnea is common in patients with HF and exposes the heart and circulation to adverse mechanical and autonomic effects. However, its effect on mortality rates of patients with HF has not been reported.

METHODS
In a prospective study involving 164 HF patients with left ventricular ejection fractions (LVEFs) Lesser than or equal to 45%, we performed polysomnography and compared death rates between those with M-NSA (apnea-hypopnea index [AHI] Lesser than 15/h of sleep) and those with untreated OSA (AHI Greater than or equal 15/h of sleep).

RESULTS
During a mean (Plus or Minus SD) of 2.9 Plus or Minus 2.2 and a maximum of 7.3 years of follow-up, the death rate was significantly greater in the 37 untreated OSA patients than in the 113 M-NSA patients after controlling for confounding factors (8.7 vs. 4.2 deaths per 100 patient-years, p = 0.029). Although there were no deaths among the 14 patients whose OSA was treated by continuous positive airway pressure (CPAP), the mortality rate was not significantly different from the untreated OSA patients (p = 0.070).

CONCLUSIONS
In patients with HF, untreated OSA is associated with an increased risk of death independently of confounding factors. (J Am Coll Cardiol 2007;49:1625–31) (c) 2007 by the American College of Cardiology Foundation

Alejandro Recio-Mayoral, MD, Marinela Chaparro, MD, Belen Prado, MD, Rocio Cozar, MD, Irene Mendez, MD, Debasish Banerjee, MD, MRCP, Juan C. Kaski, MD, DM, DSC, Jose Cubero, MD, Jose M. Cruz, MD

J Am Coll Cardiol 2007;49:1283-8

OBJECTIVES
This study was designed to determine the effectiveness of a protocol for rapid intravenous hydration to prevent contrast-induced nephropathy (CIN) in patients undergoing emergency percutaneous coronary intervention (PCI).

BACKGROUND
Contrast-induced nephropathy frequently complicates PCI, resulting in prolonged hospitalization and increased in-hospital and long-term morbidity and mortality. Little is known regarding prevention of CIN in patients undergoing urgent PCI.

METHODS
We conducted a prospective, controlled, randomized, single-center trial in 111 consecutive patients with acute coronary syndrome undergoing emergency PCI. As part of the hydration therapy, 56 patients (group A) received an infusion of sodium bicarbonate plus N-acetylcysteine (N-AC) started just before contrast injection and continued for 12 h after PCI. The remaining 55 patients (group B) received the standard hydration protocol consisting of intravenous isotonic saline for 12 h after PCI. In both groups, 2 doses of oral N-AC were administered the next day.

RESULTS
The 2 groups were similar with respect to age, gender, diabetes mellitus, and baseline serum creatinine. A serum creatinine concentration Greater Than 0.5 mg/dl from baseline after emergency PCI was observed in 1 patient in group A (1.8%) and in 12 patients in group B (21.8%; p Lesser Than 0.001). Acute anuric renal failure was observed in 1 patient (1.8%) in group A and in 7 patients (12.7%) in group B (p = 0.032).

CONCLUSIONS
Rapid intravenous hydration with sodium bicarbonate plus N-AC before contrast injection is effective and safe in the prevention of CIN in patients undergoing emergency PCI. (J Am Coll Cardiol 2007;49:1283-8) (c) 2007 by the American College of Cardiology Foundation

Ilan Goldenberg, MD, Arthur J. Moss, MD, Scott McNitt, MS, Wojciech Zareba, MD, PHD, W. Jackson Hall, PHD, Mark L. Andrews, BBS, for the MADIT-II Investigators

(J Am Coll Cardiol 2007;49:1427–33)

OBJECTIVES
This study was designed to evaluate the relationship among blood pressure (BP) levels, risk of sudden cardiac death (SCD), and benefit of the implantable cardioverter-defibrillator (ICD) in patients with ischemic left ventricular (LV) dysfunction.

BACKGROUND
Low BP has been shown to be associated with increased mortality in patients with LV dysfunction and heart failure. We hypothesized that increasing BP levels are associated with a reduction in the risk of SCD in this population, thereby limiting ICD efficacy in a lower-risk subset.

METHODS
The independent contribution of systolic blood pressure (SBP) and diastolic blood pressure (DBP) to outcome was analyzed in 1,231 patients enrolled in the prospective MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II).

RESULTS
Multivariate analysis showed that in the conventional therapy arm of the trial, 10-mm Hg increments in systolic BP were independently associated with a respective 14% (p = 0.01) and 16% (p = 0.04) reduction in the risk of cardiac mortality and SCD; similar trends were shown for DBP. Defibrillator therapy provided the least survival benefit to patients in the lower-risk, upper SBP (Greater than 130 mm Hg) and DBP (Greater than or equal to 80 mm Hg) quartiles (hazard ratio 1.04 [p = 0.89] and 1.05 [p = 0.88], respectively), whereas a respective 39% and 38% (p = 0.002) reduction in the risk of death with ICD therapy was observed among patients with lower BP values.

CONCLUSIONS
In patients with ischemic LV dysfunction, SBP and DBP levels show an inverse correlation with sudden cardiac mortality. These noninvasive hemodynamic parameters may be useful for identifying lower-risk patients, in whom the benefit of primary defibrillator implantation is more limited. (J Am Coll Cardiol 2007;49:1427–33) (c) 2007 by the American College of Cardiology Foundation

Alejandro Recio-Mayoral, MD, Marinela Chaparro, MD, Belen Prado, MD, Rocio Cozar, MD, Irene Mendez, MD, Debasish Banerjee, MD, MRCP, Juan C. Kaski, MD, DM, DSC, Jose Cubero, MD, Jose M. Cruz, MD

J Am Coll Cardiol 2007;49:1283-8

OBJECTIVES
This study was designed to determine the effectiveness of a protocol for rapid intravenous hydration to prevent contrast-induced nephropathy (CIN) in patients undergoing emergency percutaneous coronary intervention (PCI).

BACKGROUND
Contrast-induced nephropathy frequently complicates PCI, resulting in prolonged hospitalization and increased in-hospital and long-term morbidity and mortality. Little is known regarding prevention of CIN in patients undergoing urgent PCI.

METHODS
We conducted a prospective, controlled, randomized, single-center trial in 111 consecutive patients with acute coronary syndrome undergoing emergency PCI. As part of the hydration therapy, 56 patients (group A) received an infusion of sodium bicarbonate plus N-acetylcysteine (N-AC) started just before contrast injection and continued for 12 h after PCI. The remaining 55 patients (group B) received the standard hydration protocol consisting of intravenous isotonic saline for 12 h after PCI. In both groups, 2 doses of oral N-AC were administered the next day.

RESULTS
The 2 groups were similar with respect to age, gender, diabetes mellitus, and baseline serum creatinine. A serum creatinine concentration Greater Than 0.5 mg/dl from baseline after emergency PCI was observed in 1 patient in group A (1.8%) and in 12 patients in group B (21.8%; p Lesser Than 0.001). Acute anuric renal failure was observed in 1 patient (1.8%) in group A and in 7 patients (12.7%) in group B (p = 0.032).

CONCLUSIONS
Rapid intravenous hydration with sodium bicarbonate plus N-AC before contrast injection is effective and safe in the prevention of CIN in patients undergoing emergency PCI. (J Am Coll Cardiol 2007;49:1283-8) (c) 2007 by the American College of Cardiology Foundation

Michael Piorkowski, MD, Sabine Fischer, MD, Caroline Stellbaum, MD, Markus Jaster, MD, Peter Martus, PHD, Andreas J. Morguet, MD, Heinz-Peter Schultheiss, MD, Ursula Rauch, MD

Berlin, Germany

J Am Coll Cardiol 2007;49:1035-42

OBJECTIVES
We sought to test the platelet inhibitory and anti-inflammatory effects of a higher statin dosage compared with combined treatment with ezetimibe plus a low statin dose.

BACKGROUND
Reducing the level of low-density lipoprotein cholesterol (LDL-C) with statins induces important pleiotropic effects such as platelet inhibition. An insufficient LDL-C reduction often is treated with ezetimibe, an intestinal cholesterol absorption inhibitor, in combination with a low statin dose. It is not known whether this combination therapy has the same pleiotropic effects as a statin monotherapy.

METHODS
Fifty-six patients with coronary artery disease were assigned randomly to receive either 40 mg/day of atorvastatin or 10 mg/day of ezetimibe plus 10 mg/day of atorvastatin for 4 weeks. The levels of LDL-C, platelet activation markers after stimulation, platelet aggregation, and plasma chemokine levels (i.e., regulated on activation normally T-cell expressed and secreted [RANTES]) were measured before and after changing lipid-lowering medication.

RESULTS
Platelet activation markers (P-selectin) after stimulation (adenosine diphosphate) were reduced by 40 mg/day of atorvastatin (-5.2 plus-minus 1.6 arbitrary units) but not by ezetimibe plus low-dose atorvastatin (2.1 plus-minus 1.8 arbitrary units; p less than 0.005) despite a similar reduction of LDL-C (atorvastatin -1.01 plus-minus 0.18 mmol/l vs. ezetimibe plus atorvastatin -1.36 plus-minus 0.22 mmol/l, p = NS). Thrombin receptor-activating peptide-induced platelet aggregation as well as plasma RANTES levels were reduced by 40 mg/day of atorvastatin but not by ezetimibe plus low-dose atorvastatin.

CONCLUSIONS
Platelet reactivity and a proinflammatory chemokine were reduced more by the higher atorvastatin dose than by ezetimibe plus low-dose atorvastatin. In patients with coronary artery disease, it might be important to combine ezetimibe with higher statin dosages to benefit from cholesterol-independent pleiotropic effects. (J Am Coll Cardiol 2007;49:1035-42) (c) 2007 by the American College of Cardiology Foundation

Mathew S. Maurer, MD, Daniel Burkhoff, MD, PHD, Linda P. Fried, MD, MPH, John Gottdiener, MD, FACC, Donald L. King, MD, Dalane W. Kitzman, MD, FACC

New York, New York

J Am Coll Cardiol 2007;49:972-81

OBJECTIVES
The purpose of this study was to evaluate left ventricular (LV) size and structure in elderly subjects with hypertension (HTN) and heart failure who have a normal ejection fraction (HFNEF) in a large population-based sample.

BACKGROUND
The pathophysiology of HFNEF is incompletely understood but is generally attributed to LV diastolic dysfunction with normal or reduced LV diastolic chamber size despite greater than normal filling pressures.

METHODS
In the Cardiovascular Health Study (n = 5,888), demographic and clinical characteristics and ventricular structure and function were compared in healthy normal subjects (healthy; n = 499), subjects with HTN but not heart failure (HTN; n = 2,184), and subjects with HTN and HFNEF (HFNEF; n = 167).

RESULTS
Subjects with HFNEF were older, more obese, and more often African American than healthy and HTN subjects and had a higher prevalence of diabetes, coronary heart disease, and anemia than HTN subjects. Serum creatinine and cystatin-C were increased in HFNEF subjects. Average LV diastolic dimension was significantly increased in HFNEF subjects (5.2 plus-minus 0.8 cm) compared with healthy (4.8 plus-minus 0.6 cm) and HTN (4.9 plus-minus 0.6 cm) subjects. As a result, average calculated stroke volume (89 plus-minus 25 ml vs. 78 plus-minus 20 ml and 80 plus-minus 20 ml) and cardiac output (6.0 plus-minus 2.0 l/min vs. 4.8 plus-minus 1.3 l/min and 5.1 plus-minus 1.4 l/min) were increased in HFNEF compared with healthy and HTN subjects, respectively.

CONCLUSIONS
As a group, HFNEF subjects have increased LV diastolic diameter and increased calculated stroke volume. They also have increased prevalence of multiple comorbidities, including anemia, renal dysfunction, and obesity, that can cause volume overload. These data suggest that extracardiac factors, via volume overload, may contribute to the pathophysiology of HFNEF in the elderly. (J Am Coll Cardiol 2007;49:972-81) (c) 2007 by the American College of Cardiology Foundation

OBJECTIVES
This study sought to compare the safety, diagnostic efficacy, and efficiency of multi-slice computed tomography (MSCT) with standard diagnostic evaluation of low-risk acute chest pain patients.

BACKGROUND
Over 1 million patients have emergency center evaluations for acute chest pain annually, at an estimated diagnostic cost of over $10 billion. Multi-slice computed tomography has a high negative predictive value for exclusion of coronary artery stenoses.

METHODS
We randomized patients to MSCT (n = 99) versus SOC (n = 98) protocols. The MSCT patients with minimal disease were discharged; those with stenosis greater than 70% underwent catheterization, whereas cases with intermediate lesions or non-diagnostic scans underwent stress testing. Outcomes included: safety (freedom from major adverse events over 6 months), diagnostic efficacy (clinically correct and definitive diagnosis), as well as time and cost of care.

RESULTS
Both approaches were completely (100%) safe. The MSCT alone immediately excluded or identified coronary disease as the source of chest pain in 75% of patients, including 67 with normal coronary arteries and 8 with severe disease referred for invasive evaluation. The remaining 25% of patients required stress testing, owing to intermediate severity lesions or non-diagnostic scans. During the index visit, MSCT evaluation reduced diagnostic time compared with SOC (3.4 h vs. 15.0 h, p less than 0.001) and lowered costs ($1,586 vs. $1,872, p less than 0.001). Importantly, MSCT patients required fewer repeat evaluations for recurrent chest pain (MSCT, 2 of 99 (2.0%) patients vs. SOC, 7 of 99 (7%) patients; p = 0.10).

CONCLUSIONS
Multi-slice computed tomographic coronary angiography can definitively establish or exclude coronary disease as the cause of chest pain. However, inability to determine the physiological significance of intermediate severity coronary lesions and cases with inadequate image quality are present limitations. (Study of Coronary Artery Computed Tomography to Diagnose Emergency Chest Pain CR; http://clinicaltrials.gov/ct/show/NCT00273832?order.1 ; NCT00273832) (c) 2007 by the American College of Cardiology Foundation

Piotr Ponikowski, MD, PHD,Stefan D. Anker, MD, PHD, Joanna Szachniewicz, MD,Darlington Okonko, BSC, MRCP, Mark Ledwidge, PHD, Robert Zymlinski, MD,Enda Ryan, MRCP, Scott M. Wasserman, MD, Nigel Baker, MSC, Dylan Rosser, BSC,Stuart D. Rosen, MD, Philip A. Poole-Wilson, MD, Waldemar Banasiak, MD, PHD,Andrew J. S. Coats, DM, Ken McDonald, MD

J Am Coll Cardiol 2007;49:753-62

OBJECTIVES
This study sought to investigate whether darbepoetin alfa, an erythropoiesis-stimulating protein (ESP), improves exercise capacity in patients with symptomatic chronic heart failure (CHF) and anemia.

BACKGROUND
Anemia is common in patients with CHF.

METHODS
In a multicenter, randomized, double-blind, placebo-controlled study, CHF patients with anemia (hemoglobin greater than or equal to 9.0 to less than or equal to 12.0 g/dl) received subcutaneous placebo (n = 22) or darbepoetin alfa (n = 19) at a starting dose of 0.75 mg/kg every 2 weeks for 26 weeks. The primary end point was change in exercise tolerance from baseline to week 27 as measured by peak oxygen uptake (ml/min/kg body weight). Other end points included changes in absolute peak VO2 (ml/min), exercise duration, and health-related quality of life.

RESULTS
Differences (95% confidence interval) in mean changes from baseline to week 27 between treatment groups were 1.5 g/dl (0.5 to 2.4) for hemoglobin concentration (p = 0.005), 0.5 ml/kg/min (-0.7 to 1.7) for peak VO2 (p = 0.40),45 ml/min (-35 to 127) for absolute peak VO2 (p = 0.27), and 108 s (-11 to 228) for exercise duration (p = 0.075). Patients receiving darbepoetin alfa compared with placebo had an improvement in self-reported Patient's Global Assessment of Change (79% vs. 41%, p = 0.01) but no significant differences in the Kansas City Cardiomyopathy and Minnesota Living with Heart Failure Questionnaire scores. Darbepoetin alfa was well tolerated.

CONCLUSIONS
In patients with symptomatic CHF and anemia, darbepoetin alfa increased and maintained hemoglobin concentrations and improved health-related quality of life. A trend toward increased exercise time but not peak VO2 was observed. (Impact of Darbepoetin Alfa on Exercise Tolerance and Left Ventricular Structure in Subjects With Symptomatic Congestive Heart Failure (CHF) and Anemia;http://clinicaltrials.gov/ct/show/NCT00117234?order=1; NCT00117234). (c) 2007 by the American College of Cardiology Foundation

Maria Rosa Costanzo, MD, FACC, Maya E. Guglin, MD, FACC,Mitchell T. Saltzberg, MD, FACC, Mariell L. Jessup, MD, FACC, Bradley A. Bart, MD, FACC, John R. Teerlink, MD, FACC, Brian E. Jaski, MD, FACC, James C. Fang, MD, FACC, Erika D. Feller, MD, FACC, Garrie J. Haas, MD, FACC, Allen S. Anderson, MD, FACC, Michael P. Schollmeyer, DVM, Paul A. Sobotka, MD, FACC, for the UNLOAD Trial Investigators

J Am Coll Cardiol 2007;49:675-83

OBJECTIVES
This study was designed to compare the safety and efficacy of veno-venous ultrafiltration and standard intravenous diuretic therapy for hypervolemic heart failure (HF) patients.

BACKGROUND
Early ultrafiltration may be an alternative to intravenous diuretics in patients with decompensated HF and volume overload.

METHODS
Patients hospitalized for HF with greater than or equal 2 signs of hypervolemia were randomized to ultrafiltration or intravenous diuretics. Primary end points were weight loss and dyspnea assessment at 48 h after randomization. Secondary end points included net fluid loss at 48 h, functional capacity, HF rehospitalizations, and unscheduled visits in 90 days. Safety end points included changes in renal function, electrolytes, and blood pressure.

RESULTS
Two hundred patients (63 plus/- 15 years, 69 percent men, 71 percent ejection fraction less than or equal to 40 percent) were randomized to ultrafiltration or intravenous diuretics. At 48 h, weight (5.0 plus/- 3.1 kg vs. 3.1 plus/- 3.5 kg; p = 0.001) and net fluid loss (4.6 vs. 3.3 l; p = 0.001) were greater in the ultrafiltration group. Dyspnea scores were similar. At 90 days, the ultrafiltration group had fewer patients rehospitalized for HF (16 of 89 [18 percent] vs. 28 of 87 [32 percent]; p = 0.037), HF rehospitalizations (0.22 plus/- 0.54 vs. 0.46 plus/- 0.76; p = 0.022), rehospitalization days (1.4 plus/- 4.2 vs. 3.8 plus/- 8.5; p = 0.022) per patient, and unscheduled visits (14 of 65 [21 percent] vs. 29 of 66 [44 percent]; p = 0.009). No serum creatinine differences occurred between groups. Nine deaths occurred in the ultrafiltration group and 11 in the diuretics group.

CONCLUSIONS
In decompensated HF, ultrafiltration safely produces greater weight and fluid loss than intravenous diuretics, reduces 90-day resource utilization for HF, and is an effective alternative therapy. (The UNLOAD trial; http://clinicaltrials.gov/ct/show/NCT00124137?order=1; NCT00124137). (c) 2007 by the American College of Cardiology Foundation

Luis M. Moura, MD, Sandra F. Ramos, MSC, Jose L. Zamorano, MD, PHD, Isabel M. Barros, MD, Luis F. Azevedo, MD, Francisco Rocha-Goncalves, MD, PHD, Nalini M. Rajamannan, MD

Matosinhos and Oporto, Portugal; Madrid, Spain; and Chicago, Illinois

J Am Coll Cardiol 2007;49:554-61

OBJECTIVES
The objective of this study was to test the effect of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor on the progression of moderate to severe aortic stenosis as measured by echocardiography.

BACKGROUND
Recent retrospective studies support the hypothesis that statins slow the progression of aortic stenosis.

METHODS
We performed an open-label, prospective study evaluating 121 consecutive patients with asymptomatic moderate to severe aortic stenosis (aortic valve area greater than or equal to 1.0 cm2; mean age 73.7 +/- 8.9 years; 57 men and 64 women), treated with and without rosuvastatin according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Echocardiographic, serum lipid, and inflammatory markers were measured at baseline and every 6 months for 18 months.

RESULTS
Sixty-one patients (50.4%) with elevated LDL (159.7 +/- 33.4 mg/dl), aortic valve velocity (3.65 +/- 0.64 m/s), and aortic valve area (1.23 +/-0.42 cm^2) received rosuvastatin (20 mg/day), and 60 (49.6%) with a normal LDL (118.6 +/- 37.4 mg/dl), aortic valve velocity (3.62 +/- 0.61 m/s), and aortic valve area (1.20 +/- 0.35 cm2) received no statin. During a mean follow-up of 73 +/- 24 weeks, the change in aortic valve area in the control group was -0.10 +/- 0.09 cm^2/year versus -0.05 +/- 0.12 cm^2/year in the rosuvastatin group (p = 0.041). The increase in aortic valve velocity was 0.24 +/- 0.30 m/s/year in the control group and 0.04 +/- 0.38 m/s/year in the rosuvastatin group (p = 0.007). There was significant improvement in serum lipid and echocardiographic measures of aortic stenosis in the statin group.

CONCLUSIONS
Prospective treatment of aortic stenosis with rosuvastatin by targeting serum LDL slowed the hemodynamic progression of aortic stenosis. This is the first prospective study that shows a positive effect of statin therapy for this disease process. (Rosuvastatin Affecting Aortic Valve Endothelium; http://www.clinicaltrials.gov/ct/show/NCT00114491?order=1; NCT0014491). (c) 2007 by the American College of Cardiology Foundation

Andrew J. Sauer, BS, Arthur J. Moss, MD, Scott McNitt, MS, Derick R. Peterson, PHD, Wojciech Zareba, MD, PHD, Jennifer L. Robinson, MS, Ming Qi, PHD, Ilan Goldenberg, MD, Jenny B. Hobbs, BA, Michael J. Ackerman, MD, PHD, Jesaia Benhorin, MD, W. Jackson Hall, PHD, Elizabeth S. Kaufman, MD, Emanuela H. Locati, MD, PHD, Carlo Napolitano, MD, Silvia G. Priori, MD, PHD, Peter J. Schwartz, MD, Jeffrey A. Towbin, MD, G. Michael Vincent, MD, Li Zhang, MD

Rochester, New York; Rochester, Minnesota; Jerusalem, Israel; Cleveland, Ohio; Perugia and Pavia, Italy; Houston, Texas; and Salt Lake City, Utah

J Am Coll Cardiol 2007;49:329-37

OBJECTIVES
The aims of this study were: 1) to evaluate risk factors influencing the clinical course of mutation-confirmed adult patients with long QT syndrome (LQTS), 2) to study life-threatening cardiac events as a specific end point in adults, and 3) to examine the protective effect of beta-blocker therapy on cardiac events in adult LQTS patients with known cardiac channel mutations.

BACKGROUND
The clinical course and risk factors for cardiac events in genotype-confirmed adult patients with LQTS have not been previously investigated.

METHODS
The clinical characteristics of 812 mutation-confirmed LQTS patients age 18 years or older were studied with both univariate and multivariate analyses to determine the genotype-phenotype factors that influence the clinical course of adult patients with this disorder.

RESULTS
Female gender, corrected QT (QTc) interval, LQT2 genotype, and frequency of cardiac events before age 18 years were associated with increased risk of having any cardiac events between the ages of 18 and 40 years. Female gender, QTc interval greater than or equal to 500 ms, and interim syncopal events during follow-up after age 18 years were associated with significantly increased risk of life-threatening cardiac events in adulthood. Beta-blockers provided a 60% reduction in risk of any cardiac event and life-threatening events, with somewhat greater effect in higher-risk subjects.

CONCLUSIONS
The severity of LQTS in adulthood can be risk stratified with information regarding genotype, gender, QTc duration, and history of cardiac events. Beta-blockers effectively reduce but do not eliminate the risk of both syncopal and life-threatening cardiac events in adult patients with mutation-confirmed LQTS. (J Am Coll Cardiol 2007;49:329-37)(c) 2007 by the American College of Cardiology Foundation

David J. Tester, BS,* Michael J. Ackerman, MD, PHD*

Rochester, Minnesota

J Am Coll Cardiol 2007;49:240-6

OBJECTIVES
This study sought to determine the spectrum and prevalence of long QT syndrome (LQTS)-associated mutations in a large cohort of autopsy-negative sudden unexplained death (SUD).

BACKGROUND
Potentially heritable arrhythmia syndromes may explain a significant proportion of SUD in the young. Here, comprehensive postmortem LQTS genetic testing was performed in a cohort of SUD cases.

METHODS
From September 1998 to March 2004, 49 cases of SUD (30 male patients, average age at death 14.2 +/- 10.9 years) were referred by medical examiners/coroners to Mayo Clinic's Sudden Death Genomics Laboratory. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, open reading frame/splice site mutational analysis was conducted for all 8 genes implicated in the pathogenesis of either LQTS (LQT1 to LQT6) or multisystem disorders involving either QT or QU prolongation.

RESULTS
Ten LQTS-associated mutations (4 novel) were discovered in 10 SUD cases (20%, 8 female patients, average age at death 18.0 +/- 11.8 years). The LQTS susceptibility mutations LQT1 (5), LQT2 (3), and LQT3 (2) were far more common among women (8 of 18, 44%) than men (2 of 30, 6.7%, p less than 0.008). The activities at the time of SUD included sleep (5), exertion (2), auditory arousal (1), and undetermined (2). Sudden death was the sentinel event in two-thirds of the cases.

CONCLUSIONS
In this cardiac channel-focused molecular autopsy investigation of SUD, over one-third of decedents harbored a putative cardiac channel mutation: 7 previously reported to host mutations in the RyR2-encoded calcium release channel and now 10 with LQTS susceptibility mutations. Accordingly, postmortem cardiac channel genetic testing should be pursued in the evaluation of autopsy-negative SUD. (c) 2007 by the American College of Cardiology Foundation

Theodore Chow, MD, FACC,* Dean J. Kereiakes, MD, FACC,* Cheryl Bartone, BS,* Terri Booth, RN,* Edward J. Schloss, MD, FACC,* Theodore Waller, MD, FACC,* Eugene Chung, MD,* Santosh Menon, MD,* Brahmajee K. Nallamothu, MD, MPH, Paul S. Chan, MD, MSC

* Cincinnati, Ohio; and Ann Arbor, Michigan

J Am Coll Cardiol 2007;49:50-8

OBJECTIVES
This study sought to assess whether implantable cardioverter-defibrillators (ICDs) have different mortality benefits among patients with ischemic cardiomyopathy who screen negative and non-negative (positive and indeterminate) for microvolt T-wave alternans (MTWA).

BACKGROUND
Microvolt T-wave alternans has been proposed as an effective tool for risk stratification. However, no studies have examined whether ICD benefits differ by MTWA group.

METHODS
We developed a prospective cohort of 768 patients with ischemic cardiomyopathy (left ventricular ejection fraction less than or equal to 35%) and no prior sustained ventricular arrhythmia, of which 392 (51%) received ICDs. The mean follow-up time was 27 +/- 12 months. Propensity scores for ICD implantation based on the variables most likely to influence defibrillator implantation were developed for each MTWA cohort. Multivariable Cox analyses that controlled for propensity score, demographics, and clinical variables evaluated the degree to which ICDs decreased mortality risk for each MTWA group.

RESULTS
We identified 514 (67%) patients with a non-negative MTWA test result. After multivariable adjustment, ICDs were associated with lower all-cause mortality in MTWA-non-negative patients (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.27 to 0.76, p = 0.003) but not in MTWA-negative patients (HR 0.85, 95% CI 0.33 to 2.20, p = 0.73) (for interaction, p = 0.04), with the mortality benefit in MTWA-non-negative patients largely mediated through arrhythmic mortality reduction (HR 0.30, 95% CI 0.13 to 0.68, p = 0.004). The number needed to treat with an ICD for 2 years to save 1 life was 9 among MTWA-non-negative patients and 76 among MTWA-negative patients.

CONCLUSIONS
In patients with ischemic cardiomyopathy and no prior history of ventricular arrhythmia, mortality reduction with ICD implantation differs by MTWA status, with implications for risk stratification and health policy. (c) 2007 by the American College of Cardiology Foundation

John J. Mahmarian, MD, Habib A. Dakik, MD; Neil G. Filipchuk, MD, Leslee J. Shaw, PhD, Sherif S. Iskander, MD, Terrence D. Ruddy, MD, Felix Keng, MD, Milena J. Henzlova, MD, Adel Allam, MD, Lemuel A. Moye, MD, PhD, and Craig M. Pratt, MD for the ADENOSINE SESTAMIBI SPECT POST-INFARCTION EVALUATION (INSPIRE) Investigators

from The Methodist DeBakey Heart Center, Department of Cardiology, The Methodist Hospital, Houston, Texas; American University of Beirut, Beirut, Lebanon; University of Calgary, Calgary, Alberta, Canada; Cedars-Sinai Medical Center, Los Angeles, California; Cardiovascular Associates of East Texas, Tyler, Texas; University of Ottawa Heart Institute, Ottawa, Ontario, Canada; National Heart Centre , Singapore, Singapore; Mount Sinai Medical Center, New York, New York; Al-Azhar University, Cairo, Egypt, University of Texas School of Public Health, Houston, Texas

OBJECTIVES
To determine the relative benefit of intensive medical therapy as compared to coronary revascularization for suppressing scintigraphic ischemia.

BACKGROUND
Although medical therapies can reduce myocardial ischemia and improve patient survival following acute myocardial infarction, the relative benefit of medical therapy versus coronary revascularization for reducing ischemia is unknown.

METHODS
Prospective, randomized trial in 205 stable survivors of acute myocardial infarction to define the relative efficacy of an intensive medical therapy strategy versus coronary revascularization for suppressing scintigraphic ischemia as assessed by serial gated adenosine Tc-99m sestamibi myocardial perfusion tomography. All patients at baseline had large total (>20%) and ischemic (>10%) adenosine-induced left ventricular perfusion defects and an ejection fraction >35%. Imaging was performed 1-10 days of hospital admission and repeated in an identical fashion following optimization of therapy. Patients randomized to either strategy had similar baseline demographic and scintigraphic characteristics. Both intensive medical therapy and coronary revascularization induced significant but comparable reductions in total (-16.2+/-10% vs -17.8+/-12, p=NS) and ischemic (-15+/-9% vs -16.2+/-9%, p=NS) perfusion defect sizes, respectively. Likewise, a similar percentage of patients randomized to medical therapy versus coronary revascularization had suppression of adenosine-induced ischemia (80% vs 81%, p=NS).

CONCLUSIONS
Sequential adenosine sestamibi myocardial perfusion tomography can effectively monitor changes in scintigraphic ischemia following either anti-ischemic medical or coronary revascularization therapy. A strategy of intensive medical therapy is comparable to coronary revascularization for suppressing ischemia in stable patients after acute infarction who have preserved LV function.

A Multinational Study to Establish the Value of Early Adenosine Technetium-99m Sestamibi Myocardial Perfusion Imaging in Identifying a Low-Risk Group for Early Hospital Discharge Following Acute Myocardial Infarction

John J. Mahmarian, MD, FACC, Leslee J. Shaw, PhD, Neil G. Filipchuk, MD, Habib A. Dakik, MD, Sherif S. Iskander, MD, Terrence D. Ruddy, MD, Milena J. Henzlova, MD, Felix Keng, MD, Adel Allam, MD, Lemuel A. Moye, MD, PhD, and Craig M. Pratt, MD, FACC, for the ADENOSINE SESTAMIBI SPECT POSTINFARCTION EVALUATION (INSPIRE) Investigators

from The Methodist DeBakey Heart Center, Department of Cardiology, The Methodist Hospital, Houston, Texas; Cedars-Sinai Medical Center, Los Angeles, California; University of Calgary, Calgary, Alberta, Canada; American University of Beirut, Beirut, Lebanon; Cardiovascular Associates of East Texas, Tyler, Texas; University of Ottawa Heart Institute, Ottawa, Ontario, Canada; Mount Sinai Medical Center, New York, New York; National Heart Centre, Singapore, Singapore; Al-Azhar University, Cairo, Egypt; University of Texas School of Public Health, Houston, Texas

OBJECTIVES
To determine whether gated adenosine Tc-99m sestamibi myocardial perfusion tomography (ADSPECT) could accurately define risk and thereby guide therapeutic decision-making in stable survivors of acute myocardial infarction (AMI).

BACKGROUND
Controversy continues as to the role of noninvasive stress imaging in stratifying risk early after AMI.

METHODS
The Adenosine Sestamibi SPECT Post Infarction Evaluation (INSPIRE) is a prospective, multicenter trial which enrolled 728 clinically stable survivors of AMI who had gated ADSPECT within 10 days of hospital admission and subsequent 1 year follow-up. Event rates were assessed within prospectively defined INSPIRE risk groups based on the adenosine-induced left ventricular perfusion defect size, extent of ischemia, and ejection fraction.

RESULTS
Total cardiac events and death and reinfarction significantly increased within each INSPIRE risk group from low (5.4%, 1.8%), to intermediate (14%, 9.2%), to high (18.6%, 11.6%) (p less than 0.01). Event rates at 1 year were lowest in patients with the smallest perfusion defects but progressively increased when defect size exceeded 20% (p less than 0.0001). The perfusion results significantly improved risk stratification beyond that provided by clinical and ejection fraction variables. The low risk INSPIRE group, comprising one-third of all enrolled patients, had a shorter hospital stay with lower associated costs as compared to the higher risk groups (p less than 0.001).

CONCLUSIONS
Gated ADSPECT performed early after AMI can accurately identify a sizeable low risk group who have a less than 2% death and reinfarction rate at 1 year. Identifying these low risk patients for early hospital discharge may improve utilization of healthcare resources at considerable cost savings.

Harikrishna Tandri, MD,* Ernesto Castillo, MD, Victor A. Ferrari, MD, Khurram Nasir, MD,* Darshan Dalal, MD,* Chandra Bomma, MD,* Hugh Calkins, MD,* David A. Bluemke, MD, PHD

Baltimore, Maryland; and Philadelphia, Pennsylvania

J Am Coll Cardiol 2006;48:2277-84

OBJECTIVES
The purpose of this study was to determine interobserver agreement for interpretation of magnetic resonance imaging (MRI) examinations of arrhythmogenic right ventricular dysplasia (ARVD) and to determine sensitivity and specificity of fat detection versus functional parameters measured by MRI.

BACKGROUND
The interobserver variability of MRI and the relative importance of different MRI parameters (fat detection, regional and global right ventricular [RV] function) for ARVD diagnosis is unknown.

METHODS
Two experienced observers blinded to the clinical history independently analyzed MRI datasets obtained from 40 patients evaluated for ARVD. Twenty normal subjects underwent MRI and served as control subjects. The MRI scans were performed according to a standard protocol on a 1.5-T scanner. The observers reported on fat infiltration, global and regional RV function, myocardial thinning, and chamber dilatation qualitatively. The RV volumes were measured on the cine sequences.

RESULTS
Interobserver kappa scores for fat infiltration, global and regional RV function, wall thinning, and RV outflow dilatation were 0.74, 0.94, 0.89, 0.93, and 0.93, respectively. Correlation coefficients between observers for RV end-diastolic volume, end-systolic volume, and ejection fraction were 0.93, 0.94, and 0.95, respectively (p less than 0.001). Fifteen patients were diagnosed with ARVD using Task Force criteria. Sensitivity of fat infiltration, RV enlargement, and regional RV dysfunction for diagnosing ARVD was 84%, 68%, and 78%, and specificity was 79%, 96%, and 94%, respectively.

CONCLUSIONS
Qualitative assessment of RV structure and function is highly reproducible for experienced observers. Among the qualitative parameters, fat infiltration is less reproducible and lacks specificity compared with RV kinetic abnormalities. (c) 2006 by the American College of Cardiology Foundation

Ravi G. Assomull, MRCP,* Sanjay K. Prasad, MD, MRCP,* Jonathan Lyne, MRCP,* Gillian Smith, MSC,* Elizabeth D. Burman, MSC,* Mohammed Khan, MSC, MPH, Mary N. Sheppard, MD, FRCPATH, Philip A. Poole-Wilson, MD, FRCP, Dudley J. Pennell, MD, FRCP, FESC, FACC*

London, United Kingdom

J Am Coll Cardiol 2006;48:1977-85

OBJECTIVES
We studied the prognostic implications of midwall fibrosis in dilated cardiomyopathy (DCM) in a prospective longitudinal study.

BACKGROUND
Risk stratification of patients with nonischemic DCM in the era of device implantation is problematic. Approximately 30% of patients with DCM have midwall fibrosis as detected by late gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR), which may increase susceptibility to arrhythmia and progression of heart failure.

METHODS
Consecutive DCM patients (n = 101) with the presence or absence of midwall fibrosis were followed up prospectively for 658 +/- 355 days for events.

RESULTS
Midwall fibrosis was present in 35% of patients and was associated with a higher rate of the predefined primary combined end point of all-cause death and hospitalization for a cardiovascular event (hazard ratio 3.4, p = 0.01). Multivariate analysis showed midwall fibrosis as the sole significant predictor of death or hospitalization. However, there was no significant difference in all-cause mortality between the 2 groups. Midwall fibrosis also predicted secondary outcome measures of sudden cardiac death (SCD) or ventricular tachycardia (VT) (hazard ratio 5.2, p = 0.03). Midwall fibrosis remained predictive of SCD/VT after

CONCLUSIONS
In DCM, midwall fibrosis determined by CMR is a predictor of the combined end point of all-cause mortality and cardiovascular hospitalization, which is independent of ventricular remodeling. In addition, midwall fibrosis by CMR predicts SCD/VT. This suggests a potential role for CMR in the risk stratification of patients with DCM, which may have value in determining the need for device therapy. (c) 2006 by the American College of Cardiology Foundation

Michael H. Davidson, MD, FACC,* James M. McKenney, PHARMD,† Charles L. Shear, DRPH, James H. Revkin, MD, FACC

Chicago, Illinois; Richmond, Virginia; and New London, Connecticut

J Am Coll Cardiol 2006;48:1774-81

OBJECTIVES
This study was designed to evaluate the efficacy and safety of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, in subjects with low high-density lipoprotein cholesterol (HDL-C) levels.

BACKGROUND
Evidence suggests HDL-C is atheroprotective. A proven mechanism for increasing the level of HDL-C is the inhibition of CETP.

METHODS
A total of 162 subjects with below-average HDL-C (men less than 44 mg/dl; women less than 54 mg/dl) who were not taking lipid-modifying therapy were randomized to double-blind treatment with torcetrapib 10, 30, 60, or 90 mg/day or placebo (approx. 30 subjects per group).

RESULTS
The percent change from baseline to Week 8 with torcetrapib (least-squares mean difference from placebo) was dose-dependent and ranged from 9.0% to 54.5% for HDL-C (p less than or = 0.0001 for 30 mg and higher doses) and from 3.0% to -16.5% for low-density lipoprotein cholesterol (LDL-C) (p less than 0.01 for 90-mg dose). Low-density lipoprotein cholesterol lowering was less in subjects with higher (>150 mg/dl) versus lower levels of baseline triglycerides; at 60 mg, the change in LDL-C was 0.1% versus -22.2% (p less than 0.0001), respectively. Particle size for both HDL and LDL increased with torcetrapib. There were no dose-related increases in the frequency of adverse events. Significant blood pressure increases were noted in 2 of 140 subjects.

CONCLUSIONS
Torcetrapib resulted in substantial dose-dependent elevations in HDL-C, accompanied by moderate decreases in LDL-C at the higher doses. Torcetrapib was generally well tolerated. (c) 2006 by the American College of Cardiology Foundation

Efficacy and Safety of Torcetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor, in Individuals With Below-Average High-Density Lipoprotein Cholesterol Levels on a Background of Atorvastatin

James M. McKenney, PHARMD,* Michael H. Davidson, MD, FACC, Charles L. Shear, DRPH, James H. Revkin, MD, FACC

Richmond, Virginia; Chicago, Illinois; and New London, Connecticut

JAmColl Cardiol 2006;48:1782-90

OBJECTIVES
This study sought to evaluate the efficacy and safety of torcetrapib in patients with low high-density lipoprotein cholesterol (HDL-C) levels receiving background atorvastatin.

BACKGROUND
Elevating HDL-C levels may reduce the residual cardiovascular risk that is observed in patients treated with statin therapy. Torcetrapib (a cholesteryl ester transfer protein inhibitor) increases HDL-C and decreases low-density lipoprotein cholesterol (LDL-C).

METHODS
This was a multicenter, double-blind, randomized trial. Patients with below-average HDL-C (men less than 44 mg/dl; women 54 mg/dl) who were eligible for statin therapy according to National Cholesterol Education Program Adult Treatment Panel III guidelines or who had LDL-C greater than 130 mg/dl at screening entered an 8-week run-in period with atorvastatin 20 mg/day before randomization (n = 174) to torcetrapib 10, 30, 60, or 90 mg/day or placebo for 8 weeks. Atorvastatin was continued during treatment with torcetrapib.

RESULTS
After 8 weeks, the percent change from baseline with torcetrapib (least-squares mean difference from placebo) ranged from 8.3% to 40.2% for HDL-C (p less than or = 0.0001 for 30-mg and higher doses) and from 0.6% to -18.9% for LDL-C (p less than 0.01 for 60-mg and 90-mg doses). Particle size for both HDL and LDL increased with torcetrapib. The incidence of all-causality and treatment-related adverse events was similar across placebo and torcetrapib treatment groups with no evidence of a dose-related response. In some treatment groups, small increases in systolic and diastolic blood pressures were noted.

CONCLUSIONS
In statin-eligible patients, torcetrapib plus background atorvastatin resulted in substantial, dosedependent increases in HDL-C, accompanied by additional decreases in LDL-C beyond those seen with atorvastatin alone. Torcetrapib plus atorvastatin was generally well tolerated. (c) 2006 by the American College of Cardiology Foundation

Willem B. Meijboom, MD,* Nico R. Mollet, MD, PHD,* Carlos A. G. Van Mieghem, MD,* Jolanda Kluin, MD, PHD, Annick C. Weustink, MD,* Francesca Pugliese, MD,* Eleni Vourvouri, MD, PHD,* Filippo Cademartiri, MD, PHD,* Ad J. J. C. Bogers, MD, PHD, Gabriel P. Krestin, MD, PHD, Pim J. de Feyter, MD, PHD, FACC*

Rotterdam, the Netherlands

J Am Coll Cardiol 2006;48:1658-65

OBJECTIVES
We studied the diagnostic performance of 64-slice computed tomography coronary angiography (CTCA) to rule out or detect significant coronary stenosis in patients referred for valve surgery.

BACKGROUND
Invasive conventional coronary angiography (CCA) is recommended in most patients scheduled for valve surgery.

METHODS
During a 6-month period, 145 patients were prospectively identified from a consecutive patient population scheduled for valve surgery. Thirty-five patients were excluded because of CTCA criteria: irregular heart rhythm (n = 26), impaired renal function (n = 5), and known contrast allergy (n = 4). General exclusion criteria were: hospitalization in community hospital (n = 4), no need for CCA (n = 4), previous coronary artery bypass surgery (n = 1), or percutaneous coronary intervention (n = 4). Of the remaining 97 patients, 27 denied written informed consent. Thus, the study population comprised 70 patients (49 male, 21 female; mean age 63 +/- 11 years).

RESULTS
Prevalence of significant coronary artery disease, defined as having at least 1 >= 50% stenosis per patient, was 25.7%. Beta-blockers were administered in 71%, and 64% received lorazepam. The mean heart rate dropped from 72.5 +/- 12.4 to 59.5 +/- 7.5 beats/min. The mean scan time was 12.8 +/- 1.3 s. On a per-patient analysis, the sensitivity, specificity, and positive and negative predictive values were: 100% (18 of 18; 95% confidence interval [CI] 78 to 100), 92% (48 of 52; 95% CI 81 to 98), 82% (18 of 22; 95% CI 59 to 94), and 100% (48 of 48; 95% CI 91 to 100), respectively.

CONCLUSIONS
The diagnostic accuracy of 64-slice CTCA for ruling out the presence of significant coronary stenoses in patients undergoing valve surgery is excellent and allows CTCA implementation as a gatekeeper for invasive CCA in these patients. (c) 2006 by the American College of Cardiology Foundation