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INSIDE THIS ISSUE

Inside This Issue

	Quarterly Focus Issue: Prevention/Outcomes

Top Quarterly Focus Issue:... Clinical Research

Marie Therese Cooney, Alexandra L. Dudina, Ian M. Graham

In this review, Cooney and colleagues define the term "risk factor" and outline the concept of and rationale for total cardiovascular risk estimation. The characteristics of a clinically-useful risk estimation system include discrimination, reclassification, and usability, and all of these terms are defined and described with examples. The multitude of current risk estimation systems, such as Framingham, SCORE (Systematic COronary Risk Evaluation), and QRISK, are described and compared. The limitations of these systems are described, particularly the challenge of risk estimation in the young and the old.

Cardiovascular Genomic Medicine.   Risk Stratifying PAD With Biomarkers and Genetic Analyses

1228

Mary M. McDermott, Donald M. Lloyd-Jones

McDermott and Lloyd-Jones review the role of inflammation and genetic mutations in the progression of peripheral arterial disease (PAD). Patients with PAD have higher levels of circulating inflammatory biomarkers, particularly C-reactive protein, D-dimer, and interleukin-6. Some studies have linked levels of these biomarkers to worse outcomes, including more functional impairment, greater declines in the ankle brachial index, graft restenosis, and higher rates of cardiovascular mortality. While available data suggest a modest degree of heritability for PAD, the culprit gene or genes have not been consistently identified, and thus there is currently insufficient data to recommend genetic testing for PAD.

Coronary Disease Risk.   Genetic Variation in Paraoxonase Gene Linked to Risk of Cardiac Death
1238

Jakub J. Regieli, J. Wouter Jukema, Pieter A. Doevendans, Aeilko H. Zwinderman, John J. Kastelein, Diederick E. Grobbee, Yolanda van der Graaf

Paraoxonase (PON)-1 is a plasma protein residing on high-density lipoprotein (HDL) that appears to influence the antioxidant properties of HDL including the rate of oxidization of low-density lipoprotein. Regieli and colleagues investigated the effects of variation in the PON-1 gene on the long-term clinical outcome of patients with coronary artery disease (CAD). A marked allele-dose effect was visible from the survival curves. For instance, the 10-year absolute risk of death due to ischemic heart disease was 4.6% in L55 homozygote patients, whereas it was 7.1% in heterozygote patients and 10.9% in 55M homozygote patients. PON-1 gene variants influence the risk of fatal complications from CAD and suggest that this enzyme might be a target for modification.

Editorial Comment: H. Robert Superko, p. 1246

Coronary Disease Risk.   Measuring the Cardiovascular Benefit of Banning Public Smoking
1249

David G. Meyers, John S. Neuberger, Jianghua He

Secondhand smoke (SHS) acutely increases the risk of acute myocardial infarction (AMI). Several localities have recently enacted bans on smoking in public places and workplaces, but the risk reduction with these bans is not widely known. Meyers and colleagues performed a systematic literature review and meta-analysis, including studies of both small cities and country-wide interventions, to estimate the effect of workplace and public smoking bans. Overall, acute myocardial infarction (AMI) risk decreased by 17% comparing pre- and post-ban AMI rates. The risk of AMI continued to decrease by 26% annually after ban implementation. These results confirm that public smoking bans can reduce the incidence of AMI.

Editorial Comment: Steven A. Schroeder, p. 1256

Cost-Effectiveness.   Downstream Cardiac Testing After CAC Screening

1258

Leslee J. Shaw, James K. Min, Matthew Budoff, Heidi Gransar, Alan Rozanski, Sean W. Hayes, John D. Friedman, Romalisa Miranda, Nathan D. Wong, Daniel S. Berman

Despite evidence that coronary artery calcium (CAC) screening can more accurately risk stratify individuals, there remains concern that testing will beget more testing and will result in early and lifelong higher patterns of resource consumption with little clinical benefit. Shaw and colleagues followed cardiac resource utilization over 4 years in individuals who underwent CAC screening. Stress imaging was more often performed in those with CAC scores 400. Yet, 1-year invasive coronary angiography (ICA) rates were low, ranging from 0.3% for those with little to no CAC to 8.9% for those with CAC 1,000. ICA occurred exclusively in patients with a prior noninvasive procedure. In this study, CAC screening led to more frequent noninvasive testing in those with elevated scores, but was not used as a trigger for ICA.

Editorial Comment: Roger S. Blumenthal, Chao-Wei Hwang, Khurram Nasir, p. 1268

Cost-Effectiveness.   Cost Effectiveness of Enoxaparin for STEMI Treated With Fibrinolysis
1271

Leo Marcoff, Zugui Zhang, Wei Zhang, Edward Ewen, Claudine Jurkovitz, Prisca Leguet, Paul Kolm, William S. Weintraub

The ExTRACT–TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis In Myocardial Infarction 25) trial demonstrated a reduction in death or nonfatal myocardial infarction when enoxaparin was used instead of unfractionated heparin (UFH) as adjunctive therapy for fibrinolysis in ST-segment elevation myocardial infarction (STEMI) patients. This report by Marcoff and colleagues examined the cost effectiveness of the 2 agents using patient-level clinical outcomes and resource use and estimates of life expectancy gains. Index hospitalization costs were slightly lower by $126 in the enoxaparin group, while 30-day costs were slightly higher by $102. Patients on enoxaparin gained an average of 0.12 life-years, with estimated total lifetime costs $1,207 higher, resulting in an incremental cost-effectiveness ratio of $5,700 per life-year gained. These results suggest that enoxaparin is a cost-effective strategy for STEMI patients.

Quality of Care.   Use of Warfarin for Patients AF and CHF Is Less Than Optimal

1280

Jonathan P. Piccini, Adrian F. Hernandez, Xin Zhao, Manesh R. Patel, William R. Lewis, Eric D. Peterson, Gregg C. Fonarow, for the Get With The Guidelines Steering Committee and Hospitals

Heart failure (HF) increases the risk of thromboembolic events in patients with atrial fibrillation (AF). Piccini and colleagues analyzed over 72,000 HF admissions at 255 hospitals. Among eligible HF patients without contraindications, the median prevalence of warfarin therapy at discharge was 65% and did not improve during the 3.5 years of study. Major factors associated with lower odds of warfarin use at discharge included increasing age, nonwhite race, anemia, and treatment in the South. Warfarin use also varied inversely with CHADS₂ (congestive heart failure, hypertension, age >75, diabetes, and prior stroke or transient ischemic attack) score despite the increased risk of stroke with a higher CHADS₂ score. Guideline-recommended warfarin use in patients with AF and HF is less than optimal and varies significantly.

Editorial Comment: Javed Butler, Andreas Kalogeropoulos, p. 1290

Outcomes in ACS.   Gastrointestinal Bleeding Significantly Increases Risks in ACS Patients
1293

Eugenia Nikolsky, Gregg W. Stone, Ajay J. Kirtane, George D. Dangas, Alexandra J. Lansky, Brent McLaurin, A. Michael Lincoff, Frederick Feit, Jeffrey W. Moses, Martin Fahy, Steven V. Manoukian, Harvey D. White, E. Magnus Ohman, Michel E. Bertrand, David A. Cox, Roxana Mehran

Nikolsky and colleagues assessed the incidence, predictors, and outcomes of gastrointestinal bleeding (GIB) in patients with acute coronary syndromes (ACS) enrolled in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. GIB occurred in 1.3% of trial subjects and was strongly associated with 30-day all-cause mortality (hazard ratio: 4.87). Risk factors for GIB included older age, baseline anemia, longer duration of study drug administration before angiogram, smoking, ST-segment deviation, and diabetes. Almost 6% of subjects who experienced a GIB also had stent thrombosis. These findings confirm that GIB has a strong negative impact on outcomes in ACS patients.

	Clinical Research

Top Quarterly Focus Issue:... Clinical Research

 
Coronary Artery Disease.   No Benefit for PCI in Older Adults With Stable Angina The COURAGE Trial Subset Analysis
1303

Koon K. Teo, Steven P. Sedlis, William E. Boden, Robert A. O'Rourke, David J. Maron, Pamela M. Hartigan, Marcin Dada, Vipul Gupta, John A. Spertus, William J. Kostuk, Daniel S. Berman, Leslee J. Shaw, Bernard R. Chaitman, G. B. John Mancini, William S. Weintraub, on behalf of the COURAGE Trial Investigators

Older patients with coronary artery disease (CAD) are at increased risk for cardiac events compared with younger patients, but it is unclear if percutaneous coronary intervention (PCI) would improve outcomes over optimal medical therapy (OMT). Teo and colleagues report on a pre-specified analysis of outcomes in stable CAD patients stratified by age in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) trial. Patients >65 years of age had a 2- to 3-fold higher death rate, but had similar rates of myocardial infarction, stroke, and major cardiac events compared with younger patients. The addition of PCI to OMT did not improve or worsen clinical outcomes in patients 65 years of age. These data support the use of OMT as an initial management strategy for stable CAD, regardless of age.

Heart Rhythm Disorders.   Activating Autoantibodies Facilitate AF in Patients With Graves' Hyperthyroidism

1309

Stavros Stavrakis, Xichun Yu, Eugene Patterson, Shijun Huang, Sean R. Hamlett, Laura Chalmers, Reji Pappy, Madeleine W. Cunningham, Syed A. Morshed, Terry F. Davies, Ralph Lazzara, David C. Kem

Stavrakis and colleagues hypothesized that activating autoantibodies to β1-adrenergic (AAβ1AR) and activating autoantibodies to M2 muscarinic receptors (AAM2R) would increase the likelihood of atrial fibrillation (AF) complicating Graves' autoimmune hyperthyroidism. Immunoglobulin-G was purified from 38 patients with Graves' hyperthyroidism, approximately one-half of whom developed AF, and healthy controls. Both of these autoantibodies were present in 82% of AF patients compared with only 10% of Graves' patients who did not develop AF. Further studies confirmed that these autoantibodies can decrease action potential duration and enhance early afterdepolarizations. AAβ1AR and AAM2R, when present in patients with Graves' hyperthyroidism, facilitate development of AF.

Left Ventricular Deformation.   CRT Can Help to Normalize LV Twist
1317

Matteo Bertini, Nina Ajmone Marsan, Victoria Delgado, Rutger J. van Bommel, Gaetano Nucifora, C. Jan Willem Borleffs, Giuseppe Boriani, Mauro Biffi, Eduard R. Holman, Ernst E. van der Wall, Martin J. Schalij, Jeroen J. Bax

This study explored the effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) twist, which is emerging as a comprehensive index of LV function. LV twist is measured using echocardiography and speckle tracking software as the difference (in degrees) of apical and basal rotation. Subjects were studied before and after CRT. At baseline, peak LV twist in HF patients was 4.8° compared with 15° in controls. At 6-month follow-up, peak LV twist significantly improved only in CRT responders, from 4.3° to 8.5°. CRT can partially restore LV torsional mechanics by improving apical and basal rotation.

Left Ventricular Deformation.   Dynamic Obstruction Leads to Delayed Untwisting in HOCM Patients

1326

Jianwen Wang, John M. Buergler, Kumuthavally Veerasamy, Yelena P. Ashton, Sherif F. Nagueh

Wang and colleagues studied the etiology of reduced exercise capacity in patients with hypertrophic obstructive cardiomyopathy (HOCM) by measuring left ventricular (LV) twist before and after septal reduction therapy. Untwisting was significantly delayed in hypertrophic cardiomyopathy without obstruction and even longer in HOCM patients. The delayed untwisting was strongly correlated with LV end-diastolic pressure and peak oxygen consumption (VO₂). After septal reduction, untwisting occurred earlier and accounted for the increase in end-diastolic volume and peak VO₂. These results provide a mechanistic link between dynamic obstruction and poor exercise tolerance in HOCM patients.

Related Articles

Value and Limitations of Existing Scores for the Assessment of Cardiovascular Risk: A Review for Clinicians

Marie Therese Cooney, Alexandra L. Dudina, and Ian M. Graham
J. Am. Coll. Cardiol. 2009 54: 1209-1227. [Abstract] [Full Text] [PDF]

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