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INSIDE THIS ISSUE

Inside This Issue

	State-of-the-Art Paper

Top State-of-the-Art Paper Viewpoint and Commentary Clinical Research

Christine Jellis, Jennifer Martin, Jagat Narula, Thomas H. Marwick

Myocardial fibrosis is caused by extracellular matrix remodeling and leads to increased myocardial stiffness. While localized fibrosis is most often a consequence of ischemia, diffuse, reactive fibrosis may be triggered by a variety of conditions. Various imaging modalities and collagen biomarkers have been used as surrogate markers to assess the presence, extent, and activity of myocardial fibrosis. Techniques using echocardiography, cardiac magnetic resonance imaging (CMR), and nuclear imaging have been developed that can detect early features of systolic and diastolic left ventricular dysfunction and correlate with fibrosis. CMR and novel molecular imaging techniques may allow for earlier detection, prior to the development of dysfunction, and possibly for monitoring the efficacy of therapeutic interventions.

	Viewpoint and Commentary

Top State-of-the-Art Paper Viewpoint and Commentary Clinical Research

 
Viewpoint.   Asymptomatic Patients Should Be Screened for Atherosclerosis
98

Prediman K. Shah

Unheralded vaso-occlusive cardiovascular events (myocardial infarction, sudden death, and stroke) are often the first manifestation of vascular disease. Accurate identification of individuals at risk for such events is desirable, especially if it leads to risk amelioration. Shah reviews the utility of the currently used methods such as the Framingham risk score and finds them insufficient. Noninvasive imaging with either coronary calcium scoring or carotid intima-media thickness appears to add incremental value to these clinical risk scores. Improved risk stratification should lead to improved adherence and better matching of preventive interventions to the magnitude of risk.

Commentary.   No Evidence That Screening Asymptomatic Subjects Improves Outcomes
106

Michael S. Lauer

In an accompanying commentary, Lauer describes the pitfalls with widespread screening without proof that it improves outcomes with an analogy to the widespread adoption of prostate specific antigen (PSA) screening. PSA testing has vastly increased the number of men diagnosed with prostate cancer, but has not reduced the number of deaths related to prostate cancer. He posits that using imaging to detect subclinical atherosclerosis may similarly expand the diagnosed population, but randomized trials are needed to determine if this will improve outcomes.

Viewpoint.   All Patients Treated With Clopidogrel Should Undergo Genotyping
109

Samir B. Damani, Eric J. Topol

In a viewpoint paper, Damani and Topol review the recent data that implicate CYP2C19 gene variants, which reduce active metabolite levels of clopidogrel, in adverse cardiovascular events. These loss-of-function alleles have been linked to increased risk of stent thrombosis, myocardial infarction, and death. With viable alternatives to clopidogrel emerging, including higher clopidogrel maintenance and loading doses, prasugrel, and the soon-to-be-available ticagrelor, clinicians can modify antiplatelet therapy in those with at-risk gene variants if they are identified. The assays for this genotyping are now available and may potentially prevent tens of thousands of adverse cardiovascular events in the 30% to 40% of patients that harbor these loss-of-function alleles.

Commentary.   Genotyping for Clopidogrel Is Not Ready for Widespread Adoption
112

Paul A. Gurbel, Udaya S. Tantry, Alan R. Shuldiner, Dean J. Kereiakes

In a response to the viewpoint paper advocating routine genotyping for the loss-of-function CYP2C19*2 allele in patients prescribed clopidogrel, Gurbel and colleagues argue that much of the variation in clopidogrel response is not explained by the CYP2C19*2 allele. Other factors—both genetic and nongenetic—are likely to be important contributors. Platelet function is dynamic due to the influence of variable external factors, but the influence of the CYP2C19*2 allele is intrinsically constant. Thus, it may be reasonable to consider both genotyping and platelet function measurement to assess ischemic risk and to guide antiplatelet therapy. At present, there is no data to support either switching to prasugrel or using a higher dose of clopidogrel in those with the loss of function allele, and prospective clinical trials are needed to test the efficacy of personalized antiplatelet therapy.

	Clinical Research

Top State-of-the-Art Paper Viewpoint and Commentary Clinical Research

 
Interventional Cardiology.   No Evidence of Long-Term Risk for Stenting of Unprotected Left Main Disease
117

Duk-Woo Park, Ki Bae Seung, Young-Hak Kim, Jong-Young Lee, Won-Jang Kim, Soo-Jin Kang, Seung-Whan Lee, Cheol Whan Lee, Seong-Wook Park, Sung-Cheol Yun, Hyeon-Cheol Gwon, Myung-Ho Jeong, Yang-Soo Jang, Hyo-Soo Kim, Pum Joon Kim, In-Whan Seong, Hun Sik Park, Taehoon Ahn, In-Ho Chae, Seung-Jea Tahk, Wook-Sung Chung, Seung-Jung Park

Park and colleagues reviewed their data on 2,240 patients with unprotected left main coronary artery (ULMCA) disease who received coronary stents (n = 1,102; 30% with bare-metal stents and 70% with drug-eluting stents) or underwent coronary artery bypass grafting (CABG) (n = 1,138) between 2000 and 2006 and had complete follow-up data for at least 3 years (median 5.2 years). After adjustment for baseline variables, the 5-year risk of death (hazard ratio [HR]: 1.13) and the combined risk of death, Q-wave myocardial infarction, or stroke (HR: 1.07) were not significantly different. The risk of target vessel revascularization (TVR) was significantly higher in the stent group (HR: 5.1). Through 5 years of follow-up, stenting and CABG have similar rates of mortality and of the composite outcome, but higher rates of TVR for ULMCA disease.

Acute Infarction.   Adrenomedullin Is a Useful Biomarker for NSTEMI Patients

125

Onkar S. Dhillon, Sohail Q. Khan, Hafid K. Narayan, Kelvin H. Ng, Joachim Struck, Paulene A. Quinn, Nils G. Morgenthaler, Iain B. Squire, Joan E. Davies, Andreas Bergmann, Leong L. Ng

Adrenomedullin is present in multiple organs. It promotes vasodilation, diuresis, natriuresis, and an increase in cardiac output. Dhillon and colleagues assessed the prognostic value of admission and discharge mid-regional pro-adrenomedullin (sAM) levels in non–ST-segment elevation myocardial infarction (NSTEMI) patients. Multivariate models revealed that both admission and discharge levels were associated with the primary end point (hazard ratio: 9.75 admission; hazard ratio: 7.54 discharge). Admission sAM was particularly associated with early mortality. Measuring the sAM level may help to identify those NSTEMI patients most likely to benefit from aggressive intervention.

Antiplatelet Therapy.   Meta-Analysis Studies Interactions Between CYP2C19*2, PPI Use, and Clopidogrel

134

Jean-Sébastien Hulot, Jean-Philippe Collet, Johanne Silvain, Ana Pena, Anne Bellemain-Appaix, Olivier Barthélémy, Guillaume Cayla, Farzin Beygui, Gilles Montalescot

Hulot and colleagues performed meta-analyses of the association between the loss-of-function CYP2C19*2 allele and the use of proton pump inhibitors (PPIs) and cardiovascular outcomes in clopidogrel-treated patients. In nearly 12,000 subjects, carriers of the CYP2C19*2 allele (28%) had an odds ratio (OR) of 1.29 for major adverse cardiovascular events (MACE) compared with noncarriers, and ORs of 1.79 and 3.45 for mortality and stent thrombosis, respectively. PPI users (42% of nearly 20,000 subjects) had ORs of 1.41 for MACE and 1.18 for mortality compared with nonusers. The impact of PPI use was significantly influenced by the baseline cardiovascular risk and was only significant in high-risk patients. Combining data from several different sources demonstrates increased risk of cardiac events in patients treated with clopidogrel who carry the CYP2C19*2 allele and, to a lesser extent, those who use PPIs.

Congenital Heart Disease.   High Rates of Chronic Venous Insufficiency in Adults With Fontan Physiology

144

Anne Marie Valente, Ami B. Bhatt, Stephen Cook, Michael G. Earing, Deborah R. Gersony, Jamil Aboulhosn, Alexander R. Opotowsky, George Lui, Michelle Gurvitz, Dionne Graham, Susan M. Fernandes, Paul Khairy, Gary Webb, Marie Gerhard-Herman, Michael J. Landzberg, for the AARCC (Alliance for Adult Research in Congenital Cardiology) Investigators

Valente and colleagues studied the prevalence of chronic venous insufficiency (CVI) in adults with Fontan physiology. The hypothesis was that patients with Fontan physiology have chronically elevated systemic venous pressure and nonpulsatile pulmonary blood flow, which may increase the risk for CVI. In 159 adults with Fontan physiology, 54% reported symptoms of systemic venous disease, such as burning, swelling, pain, itching, or leg heaviness. A standardized protocol was used to assess the presence and severity of CVI. CVI was found in 60% of adults with Fontan physiology compared with 32% of healthy control patients. Twenty-two percent of Fontan patients had severe CVI. CVI is common in adult congenital heart disease patients with Fontan physiology and merits further investigation.

Editorial Comment: Ariane Marelli, p. 151

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Screening Asymptomatic Subjects for Subclinical Atherosclerosis: Not So Obvious

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J. Am. Coll. Cardiol. 2010 56: 106-108. [Full Text] [PDF]

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