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1.  Metabolic Profiles Predict Adverse Events Following Coronary Artery Bypass Grafting 
Clinical models incompletely predict outcomes following coronary artery bypass grafting. Novel molecular technologies may identify biomarkers to improve risk stratification. We examined whether metabolic profiles can predict adverse events in patients undergoing coronary artery bypass grafting.
The study population comprised 478 subjects from the CATHGEN biorepository of patients referred for cardiac catheterization who underwent coronary artery bypass grafting after enrollment. Targeted mass spectrometry-based profiling of 69 metabolites was performed in frozen, fasting plasma samples collected prior to surgery. Principal-components analysis and Cox proportional hazards regression modeling were used to assess the relation between metabolite factor levels and a composite outcome of post-coronary artery bypass grafting myocardial infarction, need for percutaneous coronary intervention, repeat coronary artery bypass grafting, or death.
Over a mean follow-up of 4.3 ± 2.4 years, 126 subjects (26.4%) suffered an adverse event. Three principal-components analysis-derived factors were significantly associated with adverse outcome in univariable analysis: short-chain dicarboxylacylcarnitines (factor 2, P=0.001); ketone-related metabolites (factor 5, P=0.02); and short-chain acylcarnitines (factor 6, P=0.004). These three factors remained independently predictive of adverse outcome after multivariable adjustment: factor 2 (adjusted hazard ratio 1.23; 95% confidence interval [1.10-1.38]; P<0.001), factor 5 (1.17 [1.01-1.37], P=0.04), and factor 6 (1.14 [1.02-1.27], P=0.03).
Metabolic profiles are independently associated with adverse outcomes following coronary artery bypass grafting. These profiles may represent novel biomarkers of risk that augment existing tools for risk stratification of coronary artery bypass grafting patients and may elucidate novel biochemical pathways that mediate risk.
PMCID: PMC3324120  PMID: 22306227
2.  High heritability of metabolomic profiles in families burdened with premature cardiovascular disease 
Integration of genetic and metabolic profiling holds promise for providing insight into human disease. Coronary artery disease (CAD) is strongly heritable, but the heritability of metabolomic profiles has not been evaluated in humans. We performed quantitative mass spectrometry-based metabolic profiling in 117 individuals within eight multiplex families from the GENECARD study of premature CAD. Heritabilities were calculated using variance components. We found high heritabilities for amino acids (arginine, ornithine, alanine, proline, leucine/isoleucine, valine, glutamate/glutamine, phenylalanine and glycine; h2=0.33–0.80, P=0.005–1.9 × 10−16), free fatty acids (arachidonic, palmitic, linoleic; h2=0.48–0.59, P=0.002–0.00005) and acylcarnitines (h2=0.23–0.79, P=0.05–0.0000002). Principal components analysis was used to identify metabolite clusters. Reflecting individual metabolites, several components were heritable, including components comprised of ketones, β-hydroxybutyrate and C2-acylcarnitine (h2=0.61); short- and medium-chain acylcarnitines (h2=0.39); amino acids (h2=0.44); long-chain acylcarnitines (h2=0.39) and branched-chain amino acids (h2=0.27). We report a novel finding of high heritabilities of metabolites in premature CAD, establishing a possible genetic basis for these profiles. These results have implications for understanding CAD pathophysiology and genetics.
PMCID: PMC2683717  PMID: 19357637
acylcarnitines; amino acids; heritability; cardiovascular disease; metabolomics
3.  Neuropeptide Y Gene Polymorphisms Confer Risk of Early-Onset Atherosclerosis 
PLoS Genetics  2009;5(1):e1000318.
Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). We have previously identified genetic linkage to familial CAD in the genomic region of NPY. We performed follow-up genetic, biostatistical, and functional analysis of NPY in early-onset CAD. In familial CAD (GENECARD, N = 420 families), we found increased microsatellite linkage to chromosome 7p14 (OSA LOD = 4.2, p = 0.004) in 97 earliest age-of-onset families. Tagged NPY SNPs demonstrated linkage to CAD of a 6-SNP block (LOD = 1.58–2.72), family-based association of this block with CAD (p = 0.02), and stronger linkage to CAD in the earliest age-of-onset families. Association of this 6-SNP block with CAD was validated in: (a) 556 non-familial early-onset CAD cases and 256 controls (OR 1.46–1.65, p = 0.01–0.05), showing stronger association in youngest cases (OR 1.84–2.20, p = 0.0004–0.09); and (b) GENECARD probands versus non-familial controls (OR 1.79–2.06, p = 0.003–0.02). A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04). To assess a causal role of NPY in atherosclerosis, we applied the NPY1-receptor–antagonist BIBP-3226 adventitially to endothelium-denuded carotid arteries of apolipoprotein E-deficient mice; treatment reduced atherosclerotic neointimal area by 50% (p = 0.03). Thus, NPY variants associate with atherosclerosis in two independent datasets (with strong age-of-onset effects) and show allele-specific expression with NPY levels, while NPY receptor antagonism reduces atherosclerosis in mice. We conclude that NPY contributes to atherosclerosis pathogenesis.
Author Summary
Early-onset coronary artery disease (CAD) has a very strong genetic component as evidenced by the heritable nature of this disease. However, little is known about the actual genes underlying disease risk. Neuropeptide Y (NPY) is an abundant protein in humans that has been implicated in cardiovascular disease pathophysiology, but comprehensive evaluation of the gene coding for this protein has never been pursued in cardiovascular disease. Therefore, using gene-wide evaluation of variants within the NPY gene in a family-based as well as a non-familial study, we have shown that a cluster of six related NPY genetic variants is associated with early-onset CAD risk. We then show that one of these variants, which resides within the promoter region of this gene, is associated with higher NPY levels. Finally, to further support the functional role of this gene in CAD, we find that antagonism of the primary receptor of this gene results in marked attenuation of atherosclerosis in a mouse model. In conclusion, these findings demonstrate the role of the NPY gene in cardiovascular disease risk and add important additional information about the genetic architecture of this complex disease.
PMCID: PMC2602734  PMID: 19119412
4.  Alcohol Withdrawal Prevention: A Randomized Evaluation of Lorazepam and Ethanol (AWARE) Pilot Study 
Alcohol withdrawal syndrome, characterized by a hyperadrenergic state with confusion, agitation and hallucinations, has detrimental effects on patient safety in the context of acute myocardial infarction (MI). Unexpected hospitalization and sudden cessation of alcohol consumption may result in adverse outcomes including in-hospital complications, increased length of stay, and death. Strategies for safe and effective patient management have not been rigorously studied.
We conducted a randomized evaluation of lorazepam and ethanol/lorazepam to evaluate the safety and efficacy of two strategies for the prevention of alcohol withdrawal syndrome in patients with acute coronary syndromes.
Patients (n=57) with myocardial infarction were screened for alcohol dependence using the CAGE questionnaire and randomized to lorazepam or to ethanol with lorazepam. Demographic group differences and complication rates were analyzed using chi square (categorical variables) and t-tests (continuous variables). Safety (composite complication rates) of the treatment strategy was evaluated using Fisher’s exact test. Length of stay was analyzed using Wilcoxon rank-sum test.
Safety-associated complication rates (self-extubation, delirium tremens, re-infarction) were not different between groups (24% lorazepam vs. 18% ethanol; p=0.56). A trend toward fewer complications in the ethanol group was noted. In addition, no difference was detected between the treatment groups for days spent in the CCU (6.9% lorazepam vs. 2.4% ethanol; p = 0.32) or overall hospital stay (6.2% lorazepam vs. 6.4% ethanol; p = 0.72).
These findings suggest that a randomized evaluation of treatment strategies to prevent complications associated with alcohol withdrawal in acute MI is safe and feasible. A larger study may provide important evidence for improving clinical outcomes for patients experiencing alcohol withdrawal during acute myocardial infarction.
PMCID: PMC4324835  PMID: 23996419
lorazepam; ethanol; alcohol withdrawal syndrome; randomized controlled trial; patient safety; acute myocardial infarction; CAGE questionnaire
5.  Improving diabetes medication adherence: successful, scalable interventions 
Effective medications are a cornerstone of prevention and disease treatment, yet only about half of patients take their medications as prescribed, resulting in a common and costly public health challenge for the US health care system. Since poor medication adherence is a complex problem with many contributing causes, there is no one universal solution. This paper describes interventions that were not only effective in improving medication adherence among patients with diabetes, but were also potentially scalable (ie, easy to implement to a large population). We identify key characteristics that make these interventions effective and scalable. This information is intended to inform health care systems seeking proven, low resource, cost-effective solutions to improve medication adherence.
PMCID: PMC4315534
medication adherence; diabetes mellitus; chronic disease; dissemination research; implementation research; review
6.  Regional systems of care demonstration project: Mission: Lifeline STEMI Systems Accelerator: Design and methodology 
American heart journal  2013;167(1):15-21.e3.
ST-segment elevation myocardial infarction (STEMI) systems of care have been associated with significant improvement in use and timeliness of reperfusion. Consequently, national guidelines recommend that each community should develop a regional STEMI care system. However, significant barriers continue to impede widespread establishment of regional STEMI care systems in the United States. We designed the Regional Systems of Care Demonstration Project: Mission: Lifeline STEMI Systems Accelerator, a national educational outcome research study in collaboration with the American Heart Association, to comprehensively accelerate the implementation of STEMI care systems in 17 major metropolitan regions encompassing >1,500 emergency medical service agencies and 450 hospitals across the United States. The goals of the program are to identify regional gaps, barriers, and inefficiencies in STEMI care and to devise strategies to implement proven recommendations to enhance the quality and consistency of care. The study interventions, facilitated by national faculty with expertise in regional STEMI system organization in partnership with American Heart Association representatives, draw upon specific resources with proven past effectiveness in augmenting regional organization. These include bringing together leading regional health care providers and institutions to establish common commitment to STEMI care improvement, developing consensus-based standardized protocols in accordance with national professional guidelines to address local needs, and collecting and regularly reviewing regional data to identify areas for improvement. Interventions focus on each component of the reperfusion process: the emergency medical service, the emergency department, the catheterization laboratory, and inter-hospital transfer. The impact of regionalization of STEMI care on clinical outcomes will be evaluated.
PMCID: PMC3936880  PMID: 24332137
7.  Identifying Factors that Influence Hospital Length of Stay in Patients with Non-ST-segment Elevation Myocardial Infarction: Insights from the Acute Coronary Treatment Intervention Outcomes Network Registry®-Get With The Guidelines™ 
The American journal of medicine  2012;125(11):10.1016/j.amjmed.2012.04.038.
Substantial heterogeneity in hospital length of stay (LOS) exists among patients admitted with non-ST-segment elevation myocardial infarction (NSTEMI). Furthermore, little is known about the factors that impact LOS and our ability to modify them.
We examined 39,107 NSTEMI patients admitted to 351 ACTION Registry®-GWTG™ hospitals from 1/1/07–3/31/09 who underwent cardiac catheterization and survived to discharge. Length of stay was categorized into four groups (≤2, 3–4, 5–7, and ≥8 days), where prolonged LOS was defined as >4 days.
The overall median (25th, 75th) LOS was 3 (2, 5) days. Patients with a LOS of >2 days were older with more comorbidities, but were less likely to receive evidence-based therapies or percutaneous coronary intervention (PCI). Among the factors associated with prolonged LOS >4 days were delay to cardiac catheterization >48 hours, heart failure or shock on admission, female gender, insurance type, and admission to the hospital on a Friday afternoon or evening. Hospital characteristics such as number of beds, academic versus non-academic, or urban versus rural setting, were not associated with prolonged LOS.
Patients with longer LOS have more comorbidities and in-hospital complications, yet paradoxically, are less often treated with evidence-based medications and are less likely to receive PCI. Hospital admission on a Friday afternoon or evening and delays to catheterization appear to significantly impact LOS. A better understanding of factors associated with LOS in patients with NSTEMI is needed to promote safe and early discharge in an era of increasingly restrictive healthcare resources.
PMCID: PMC3884687  PMID: 22921886
non-ST-segment elevation myocardial infarction; length of stay; hospital discharge
8.  Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm 
Gretarsdottir, Solveig | Baas, Annette F | Thorleifsson, Gudmar | Holm, Hilma | den Heijer, Martin | de Vries, Jean-Paul P M | Kranendonk, Steef E | Zeebregts, Clark J A M | van Sterkenburg, Steven M | Geelkerken, Robert H | van Rij, Andre M | Williams, Michael J A | Boll, Albert P M | Kostic, Jelena P | Jonasdottir, Adalbjorg | Jonasdottir, Aslaug | Walters, G Bragi | Masson, Gisli | Sulem, Patrick | Saemundsdottir, Jona | Mouy, Magali | Magnusson, Kristinn P | Tromp, Gerard | Elmore, James R | Sakalihasan, Natzi | Limet, Raymond | Defraigne, Jean-Olivier | Ferrell, Robert E | Ronkainen, Antti | Ruigrok, Ynte M | Wijmenga, Cisca | Grobbee, Diederick E | Shah, Svati H | Granger, Christopher B | Quyyumi, Arshed A | Vaccarino, Viola | Patel, Riyaz S | Zafari, A Maziar | Levey, Allan I | Austin, Harland | Girelli, Domenico | Pignatti, Pier Franco | Olivieri, Oliviero | Martinelli, Nicola | Malerba, Giovanni | Trabetti, Elisabetta | Becker, Lewis C | Becker, Diane M | Reilly, Muredach P | Rader, Daniel J | Mueller, Thomas | Dieplinger, Benjamin | Haltmayer, Meinhard | Urbonavicius, Sigitas | Lindblad, Bengt | Gottsäter, Anders | Gaetani, Eleonora | Pola, Roberto | Wells, Philip | Rodger, Marc | Forgie, Melissa | Langlois, Nicole | Corral, Javier | Vicente, Vicente | Fontcuberta, Jordi | España, Francisco | Grarup, Niels | Jørgensen, Torben | Witte, Daniel R | Hansen, Torben | Pedersen, Oluf | Aben, Katja K | de Graaf, Jacqueline | Holewijn, Suzanne | Folkersen, Lasse | Franco-Cereceda, Anders | Eriksson, Per | Collier, David A | Stefansson, Hreinn | Steinthorsdottir, Valgerdur | Rafnar, Thorunn | Valdimarsson, Einar M | Magnadottir, Hulda B | Sveinbjornsdottir, Sigurlaug | Olafsson, Isleifur | Magnusson, Magnus Karl | Palmason, Robert | Haraldsdottir, Vilhelmina | Andersen, Karl | Onundarson, Pall T | Thorgeirsson, Gudmundur | Kiemeney, Lambertus A | Powell, Janet T | Carey, David J | Kuivaniemi, Helena | Lindholt, Jes S | Jones, Gregory T | Kong, Augustine | Blankensteijn, Jan D | Matthiasson, Stefan E | Thorsteinsdottir, Unnur | Stefansson, Kari
Nature genetics  2010;42(8):692-697.
We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 × 10−10. In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 × 10−5), peripheral arterial disease (OR = 1.14, P = 3.9 × 10−5) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases—that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
PMCID: PMC4157066  PMID: 20622881
9.  Risk assessment in the genomic era: Are we missing the low-hanging fruit? 
American heart journal  2009;157(5):799-801.
PMCID: PMC3976901  PMID: 19376302
10.  Medication Adherence: A Call for Action 
American heart journal  2011;162(3):412-424.
Poor adherence to efficacious cardiovascular related medications has led to considerable morbidity, mortality, and avoidable health care costs. This paper provides results of a recent think tank meeting in which various stakeholder groups representing key experts from consumers, community health providers, the academic community, decision-making government officials (FDA, NIH, etc), and industry scientists met to evaluate the current status of medication adherence and provide recommendations for improving outcomes. Below, we review the magnitude of the problem of medication adherence, prevalence, impact, and cost. We then summarize proven effective approaches and conclude with a discussion of recommendations to address this growing and significant public health issue of medication non adherence.
PMCID: PMC3947508  PMID: 21884856
11.  Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial 
European Heart Journal  2014;35(28):1864-1872.
The risk of stroke in patients with atrial fibrillation (AF) increases with age. In the ARISTOTLE trial, apixaban when compared with warfarin reduced the rate of stroke, death, and bleeding. We evaluated these outcomes in relation to patient age.
Methods and results
A total of 18 201 patients with AF and a raised risk of stroke were randomized to warfarin or apixaban 5 mg b.d. with dose reduction to 2.5 mg b.d. or placebo in 831 patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, or creatinine ≥133 μmol/L. We used Cox models to compare outcomes in relation to patient age during 1.8 years median follow-up. Of the trial population, 30% were <65 years, 39% were 65 to <75, and 31% were ≥75 years. The rates of stroke, all-cause death, and major bleeding were higher in the older age groups (P < 0.001 for all). Apixaban was more effective than warfarin in preventing stroke and reducing mortality across all age groups, and associated with less major bleeding, less total bleeding, and less intracranial haemorrhage regardless of age (P interaction >0.11 for all). Results were also consistent for the 13% of patients ≥80 years. No significant interaction with apixaban dose was found with respect to treatment effect on major outcomes.
The benefits of apixaban vs. warfarin were consistent in patients with AF regardless of age. Owing to the higher risk at older age, the absolute benefits of apixaban were greater in the elderly.
PMCID: PMC4104493  PMID: 24561548
Atrial fibrillation; Age; Anticoagulants; Stroke; Bleeding; Apixaban
12.  Serious Infection Following Acute Myocardial Infarction: Incidence, Clinical Features, and Outcomes 
JACC. Cardiovascular interventions  2012;5(7):10.1016/j.jcin.2012.03.018.
Little is known about the incidence, location, etiologic organisms, and outcomes of infection in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI).
To address this knowledge gap using the database of the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. We also assessed the association between serious infections and 90-day death or death/MI.
We analyzed data from 5745 STEMI patients enrolled in the APEX-AMI trial. Detailed information on infection was collected on all patients. We describe characteristics of patients according to infection and details of infection. Cox proportional hazards models were used to assess 90-day outcomes among patients with and without infections after adjusting for associated clinical variables and using infection as a time-dependent covariate.
Overall, 138 patients developed a serious infection (2.4%), most of whom presented with a single-site infection. The median (25th, 75th percentile) time until diagnosis of infection was 3 (1, 6) days. The most commonly identified organism was Staphylococcus aureus, and the main location of infection was the bloodstream. These patients had more comorbidities and lower procedural success at index PCI than those without infections. Serious infection was associated with significantly higher rates of 90-day death (adjusted hazard ratio [HR] 5.6; 95% confidence interval [CI] 3.8-8.4) and death or MI (adjusted HR 4.9; 95% CI 3.4-7.1).
Infections complicating the course of patients with STEMI are uncommon but associated with markedly worse 90-day clinical outcomes. Mechanisms for early identification of these high-risk patients, as well as design of strategies to reduce their risk of infection, are warranted.
PMCID: PMC3883036  PMID: 22814783
ST-segment elevation myocardial infarction; percutaneous coronary intervention; infection; outcomes
13.  Atrial Fibrillation: A Review of Recent Studies with a Focus on Those from the Duke Clinical Research Institute 
Scientifica  2014;2014:901586.
Atrial fibrillation is the most common arrhythmia and accounts for one-third of hospitalizations for rhythm disorders in the United States. The prevalence of atrial fibrillation averages 1% and increases with age. With the aging of the population, the number of patients with atrial fibrillation is expected to increase 150% by 2050, with more than 50% of atrial fibrillation patients being over the age of 80. This increasing burden of atrial fibrillation will lead to a higher incidence of stroke, as patients with atrial fibrillation have a five- to sevenfold greater risk of stroke than the general population. Strokes secondary to atrial fibrillation have a worse prognosis than in patients without atrial fibrillation. Vitamin K antagonists (e.g., warfarin), direct thrombin inhibitors (dabigatran), and factor Xa inhibitors (rivaroxaban and apixaban) are all oral anticoagulants that have been FDA approved for the prevention of stroke in atrial fibrillation. This review will summarize the experience of anticoagulants in patients with atrial fibrillation with a focus on the experience at the Duke Clinic Research Institute.
PMCID: PMC4152955  PMID: 25215263
14.  Antithrombotic therapy for atrial fibrillation and coronary artery disease in older patients 
American heart journal  2012;164(4):607-615.
Older patients with atrial fibrillation (AF) and coronary artery disease (CAD) face high risk of stroke and bleeding with antithrombotic therapy. Balancing safe and effective use of aspirin, clopidogrel, and warfarin in this population is important.
From the Duke Databank for Cardiovascular Disease, we identified patients with AF ≥65 years old with angiographically confirmed CAD from 2000 to 2010. Antithrombotic use was described across age and Congestive heart failure, Hypertension, Age >75 years, Diabetes, prior Stroke/transient ischemic attack (CHADS2) stroke risk and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding scores. Death and the composite of death, myocardial infarction, and stroke by antithrombotic strategy were reported.
Of 2,122 patients ≥65 years old with AF and CAD, 477 (22.5%) were ≥80 years old; 1,133 (53.4%) had acute coronary syndromes. Overall rates of aspirin, clopidogrel, and warfarin use were 83.4%, 34.6%, and 38.9%, respectively. Compared with patients 65 to 79 years old, more patients ≥80 years old were at high stroke risk (CHADS2 ≥2, 84.7% vs 57.8%) and high bleeding risk (ATRIA 5-10, 55.8% vs 23.3%). Warfarin use in both age groups increased with higher CHADS2 scores and decreased with higher ATRIA scores. Of patients ≥80 years old with CHADS2 ≥2, 150 (38.2%) received warfarin. Antithrombotic strategy was not associated with improved 1-year adjusted outcomes.
Among older patients with AF and CAD, overall warfarin use was low. Patients ≥80 years old at highest stroke risk received warfarin in similar proportions to the overall cohort. Further investigation into optimizing antithrombotic strategies in this population is warranted.
PMCID: PMC3777661  PMID: 23067921
15.  Differences in Level of Care at the End of Life According to Race 
Tailoring care for patients and their families at the end-of-life is an important goal. This study examined factors associated with patient choices for level of care at the end of life.
Demographic data and level of care (full code, do not resuscitate, or withdrawal of life support) were collected on 1072 patients who died from January 1998 to June 2006 on a cardiac care unit. Logistic regression was used to identify factors associated with level of care.
Of 15,402 patients admitted during the study, 1072 died, comprising the study sample. Median age of blacks was 64 years (IQR, 50, 74) and whites, 70 years (IQR, 62, 78). At the time of death the level of care differed significantly in blacks versus whites. 41.8% (n = 112) of blacks versus 26.7% (n = 194) of whites chose full code (p <.0001); 37.3% (n = 96) of blacks versus 43.9% (n = 317) whites chose DNR (p = .026); and 20.9% (n=54) of blacks versus 29.3% (n=210) of whites chose withdrawal of life support (p = .005). After controlling for age, sex, diagnosis, length of intensive care stay, and length of hospital stay, blacks were more likely than whites to choose full code status at the time of death (OR 1.91 [95% CI, 2.63 – 1.39], p <0.0001).
Blacks are 1.9 times as likely as others to choose full code at time of death. These results suggest the need to acknowledge cultural differences when providing end of life care.
PMCID: PMC3766528  PMID: 20595215
End of life; disparities; race; withdrawal of life support; do not resuscitate; full code
16.  Physical activity in patients with stable coronary heart disease: an international perspective 
European Heart Journal  2013;34(42):3286-3293.
Despite the known benefits of regular exercise, the reasons why many coronary heart disease (CHD) patients engage in little physical activity are not well understood. This study identifies factors associated with low activity levels in individuals with chronic CHD participating in the STABILITY study, a global clinical outcomes trial evaluating the lipoprotein phospholipaseA2 inhibitor darapladib.
Methods and results
Prior to randomization, 15 486 (97.8%) participants from 39 countries completed a lifestyle questionnaire. Total physical activity was estimated from individual subject self-reports of hours spend each week on mild, moderate, and vigorous exercise, corresponding approximately to 2, 4, and 8 METS, respectively. Multivariate logistic regression evaluated clinical and demographic variables for the lowest compared with higher overall exercise levels, and for individuals who decreased rather than maintained or increased activity since diagnosis of CHD. The least active 5280 subjects (34%) reported exercise of ≤24MET.h/week. A total of 7191 subjects (46%) reported less exercise compared with before diagnosis of CHD. The majority of participants were either ‘not limited’ or ‘limited a little’ walking 100 m (84%), climbing one flight of stairs (82%), or walking 1 km/½ mile (68%), and <10% were limited ‘a lot’ by dyspnoea or angina. Variables independently associated with both low physical activity and decreasing exercise after diagnosis of CHD included more co-morbid conditions, poorer general health, fewer years of education, race, and country (P < 0.001 for all).
In this international study, low physical activity was only partly explained by cardiovascular symptoms. Potentially modifiable societal and health system factors are important determinants of physical inactivity in patients with chronic CHD.
PMCID: PMC3819591  PMID: 24014220
Physical activity; Exercise; Coronary artery disease; Cardiac rehabilitation
17.  Management and outcomes of patients presenting with STEMI by use of chronic oral anticoagulation: results from the GRACE registry 
To describe the characteristics, treatment, and mortality in patients with ST-elevation myocardial infarction (STEMI) by use of chronic oral anticoagulant (OAC) therapy.
Using data from the Global Registry of Acute Coronary Syndromes (GRACE), patient characteristics, treatment, and reperfusion strategies of STEMI patients on chronic OAC are described, and relevant variables compared with patients not on chronic OAC. Six-month post-discharge mortality rates were evaluated by Cox proportional hazard models.
Of 19,094 patients with STEMI, 574 (3.0%) were on chronic OAC at admission. Compared with OAC non-users, OAC users were older (mean age 73 vs. 65 years), more likely to be female (37 vs. 29%), were more likely to have a history of atrial fibrillation, prosthetic heart valve, venous thromboembolism, or stroke/transient ischaemic attack, had a higher mean GRACE risk score (166 vs. 145), were less likely to be Killip class I (68 vs. 82%), and were less likely to undergo catheterization/percutaneous coronary intervention (52 vs. 66%, respectively). Of the patients who underwent catheterization, fewer OAC users had the procedure done within 24 h of admission (56.5 vs. 64.5% of OAC non-users). In propensity-matched analyses (n=606), rates of in-hospital major bleeding and in-hospital and 6-month post-discharge mortality were similar for OAC users and OAC non-users (2.7 and 3.7%, p=0.64; 15 and 13%, p=0.56; 15 and 12%, p=0.47, respectively), rates of in-hospital recurrent myocardial infarction (8.6 and 2.0%, p<0.001) and atrial fibrillation (32 and 22%, p=0.004) were higher in OAC patients, and rates of 6-month stroke were lower (0.6 and 4.3%, p=0.038). Patients in both groups who underwent catheterization had lower mortality than those who did not undergo catheterization.
This is the largest study to describe the characteristics and treatment of STEMI patients on chronic OAC. The findings suggest that patients on chronic OAC are less likely to receive guideline-indicated management, but have similar adjusted rates of in-hospital and 6-month mortality.
PMCID: PMC3821815  PMID: 24222840
Acute coronary syndrome; anticoagulant; guidelines; myocardial infarction
18.  ALOX5AP Variants are Associated with In-Stent Restenosis After Percutaneous Coronary Intervention 
Atherosclerosis  2008;201(1):148-154.
Use of drug-eluting stents (DES) has reduced in-stent restenosis after percutaneous coronary intervention (PCI); however, DES are associated with late stent thrombosis. There is no accurate way to predict in-stent restenosis, although risk factors for atherosclerosis overlap those for in-stent restenosis. Therefore, we evaluated atherosclerosis candidate genes for association with in-stent restenosis.
We identified 46 consecutive cases that had undergone PCI with bare-metal stents who subsequently developed symptomatic in-stent restenosis of the target lesion (≥75% luminal narrowing) within six months. Forty-six age-, race-, vessel-diameter- and sex-matched controls without in-stent restenosis after PCI with bare-metal stent were also identified. Single-nucleotide polymorphisms (SNPs, N=82) from 39 candidate atherosclerosis genes were genotyped. Multivariable logistic regression models were used to test for association.
Five SNPs were associated with in-stent restenosis. Three ALOX5AP SNPs were most strongly associated, two with increased risk (OR 3.74, p=0.01; OR 3.46, p=0.02), and the third with decreased risk of in-stent restenosis (OR 0.09, p=0.004). Two ALOX5AP haplotypes were associated with in-stent restenosis (HapB: OR 3.13, p=0.03); and a haplotype similar to HapA: OR 0.14, p=0.0009).
ALOX5AP, a gene within the inflammatory leukotriene pathway linked to and associated with coronary atherosclerosis, is also associated with in-stent restenosis. Genotyping these variants may help identify those at risk for in-stent restenosis who would benefit most from use of DES.
PMCID: PMC3733458  PMID: 18374923
Genetics; Stent Restenosis; Coronary Artery Disease; Inflammation
19.  Transfer Times and Outcomes in ST-Elevations Myocardial Infarction Patients Undergoing Inter-Hospital Transfer for Primary Percutaneous Coronary Intervention: APEX-AMI Insights 
Transfer delays for primary percutaneous coronary intervention (PPCI) may increase mortality in patients with ST-segment elevation myocardial infarction (STEMI). We examined the association between door 1 to door 2 (D1D2) time, a measure capturing the entire transfer process, and outcomes in patients undergoing inter-hospital transfer for primary PCI.
Methods and Results
We evaluated the relationship between D1D2 time and the 90 day incidence of death, shock, and heart failure in the sub-set of 2075 (36.1%) of 5745 patients who underwent inter-hospital transfer for PPCI in the APEX-AMI trial. There was no significant difference in the 90 day incidence of death, shock, and heart failure between the transferred and the non-transferred groups (10.3% vs 10.2%, p=0.89). The median difference in symptom to balloon time between the two groups was 45 minutes (229 vs 184, p<0.001). The primary outcome per 30 minute delay was higher for patients with a D1D2 time ≤ 150 minutes (HR 1.19: 95% Confidence Interval [CI], 1.06 to 1.33 p=0.004) but not for D1D2 times > 150 minutes (HR, 0.99: 95% CI, 0.96 to 1.02; p=0.496). The association between longer D1D2 time and worsening outcome was no longer statistically significant after multivariable adjustment.
Longer transfer times were associated with higher rate of death, shock, and heart failure among patients undergoing inter-hospital transfer from PPCI, although this difference did not persist after adjusting for baseline characteristics.
Clinical Trial Registration Information
URL:, Unique Identifier: NCT00091637
PMCID: PMC3571720  PMID: 22589297
STEMI; Primary PCI; Transfer
20.  Methods of creatine kinase-MB analysis to predict mortality in patients with myocardial infarction treated with reperfusion therapy 
Trials  2013;14:123.
Larger infarct size measured by creatine kinase (CK)-MB release is associated with higher mortality and has been used as an important surrogate endpoint in the evaluation of new treatments for ST-segment elevation myocardial infarction (STEMI). Traditional approaches to quantify infarct size include the observed CK-MB peak and calculated CK-MB area under the curve (AUC). We evaluated alternative approaches to quantifying infarct size using CK-MB values, and the relationship between infarct size and clinical outcomes.
Of 1,850 STEMI patients treated with reperfusion therapy in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) (percutaneous coronary intervention (PCI)-treated) and the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) (fibrinolytic-treated) trials, 1,718 (92.9%) (COMMA, n = 868; COMPLY, n = 850) had at least five of nine protocol-required CK-MB measures. In addition to traditional methods, curve-fitting techniques were used to determine CK-MB AUC and estimated peak CK-MB. Cox proportional hazards modeling assessed the univariable associations between infarct size and mortality, and the composite of death, heart failure, shock and stroke at 90 days.
In COMPLY, CK-MB measures by all methods were significantly associated with higher mortality (hazard ratio range per 1,000 units increase: 1.09 to 1.13; hazard ratio range per 1 standard deviation increase: 1.41 to 1.62; P <0.01 for all analyses). In COMMA, the associations were similar but did not reach statistical significance. For the composite outcome of 90-day death, heart failure, shock and stroke, the associations with all CK-MB measures were statistically significant in both the COMMA and COMPLY trials.
Sophisticated curve modeling is an alternative to infarct-size quantification in STEMI patients, but it provides information similar to that of more traditional methods. Future studies will determine whether the same conclusion applies in circumstances other than STEMI, or to studies with different frequencies and patterns of CK-MB data collection.
PMCID: PMC3662641  PMID: 23782531
Creatine kinase-MB; Infarct size; ST-segment elevation myocardial infarction; Clinical outcomes
21.  Transport Time and Care Processes for Patients Transferred With ST-Segment–Elevation Myocardial Infarction 
For patients with ST-segment–elevation myocardial infarction transferred for primary percutaneous coronary intervention, guidelines have called for device activation within 90 minutes of initial presentation. Fewer than 20% of transferred patients are treated in such a timely fashion. We examine the association between transfer drive times and first door-to-device (D2D) times in a network of North Carolina hospitals. We compare the feasibility of timely percutaneous coronary intervention using ground versus air transfer.
Methods and Results
We perform a retrospective analysis of the relationship between transfer drive times and D2D times in a 119-hospital ST-segment–elevation myocardial infarction statewide network. Between July 2008 and December 2009, 1537 ST-segment–elevation myocardial infarction patients underwent interhospital transfer for reperfusion via primary percutaneous coronary intervention. For ground transfers, median D2D time was 93 minutes for drive times ≤30 minutes, 117 minutes for drive times of 31 to 45 minutes, and 121 minutes for drive times >45 minutes. For air transfers, median D2D time was 125 minutes for drive times of 31 to 45 minutes and 138 minutes for drive times >45 minutes. Helicopter transport was associated with longer door-in door-out times and, ultimately, was associated with median D2D times that exceeded guideline recommendations, no matter the transfer drive time category.
In a well-developed ST-segment–elevation myocardial infarction system, D2D times within 90 to 120 minutes appear most feasible for hospitals within 30-minute transfer drive time. Helicopter transport did not offer D2D time advantages for transferred STEMI patients. This finding appears to be attributable to comparably longer door-in door-out times for air transfers.
PMCID: PMC3600977  PMID: 22872054
acute myocardial infarction; primary coronary intervention; fibrinolysis; door to device time; transfer
22.  Organization and staffing practices in US cardiac intensive care units: a survey on behalf of the American Heart Association Writing Group on the Evolution of Critical Care Cardiology 
The cardiac intensive care unit (CICU) has evolved into a complex patient-care environment with escalating acuity and increasing utilization of advanced technologies. These changing demographics of care may require greater clinical expertise among physician providers. Despite these changes, little is known about present-day staffing practices in US CICUs.
Methods and Results:
We conducted a survey of 178 medical directors of ICUs caring for cardiac patients to assess unit structure and physician staffing practices. Data were obtained from 123 CICUs (69% response rate) that were mostly from academic medical centres. A majority of hospitals utilized a dedicated CICU (68%) and approximately half of those hospitals employed a ‘closed’ unit model. In 46% of CICUs, an intensivist consult was available, but not routinely involved in care of critically ill cardiovascular patients, while 11% did not have a board-certified intensivist available for consultation. Most CICU directors (87%) surveyed agreed that a closed ICU structure provided better care than an open ICU and 81% of respondents identified an unmet need for cardiologists with critical care training.
We report contemporary structural models and staffing practices in a sample of US ICUs caring for critically ill cardiovascular patients. Although most hospitals surveyed had dedicated CICUs, a minority of CICUs employed a ‘closed’ CICU model and few had routine intensivist staffing. Most CICU directors agree that there is a need for cardiologists with intensivist training and expertise. These survey data reveal potential areas for continued improvement in US CICU organizational structure and physician staffing.
PMCID: PMC3760580  PMID: 24062928
Cardiac intensive care; cardiovascular medicine; critical care; staffing models
23.  A Genome Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex 
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with CAD and/or MI risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.
Methods and Results
We performed a discovery meta-analysis of 5 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome wide significance in the combined analysis (rs3869109; pdiscovery=3.3×10−7, preplication=5.3×10−4 pcombined=1.12×10−9). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1×10-10 versus 3.2×10-7) suggesting the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity and self cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
PMCID: PMC3335297  PMID: 22319020
coronary artery disease; myocardial infarction; meta-analysis; genetics
24.  A Genome Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex 
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with CAD and/or MI risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.
Methods and Results
We performed a discovery meta-analysis of 5 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome wide significance in the combined analysis (rs3869109; pdiscovery=3.3×10−7, preplication=5.3×10−4 pcombined=1.12×10−9). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1×10−10 versus 3.2×10−7) suggesting the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity and self cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
PMCID: PMC3335297  PMID: 22319020
Coronary Artery Disease; Myocardial Infarction; Meta-Analysis; Genetics
25.  Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5 
BMC Genetics  2012;13:12.
Coronary artery disease (CAD), and one of its intermediate risk factors, dyslipidemia, possess a demonstrable genetic component, although the genetic architecture is incompletely defined. We previously reported a linkage peak on chromosome 5q31-33 for early-onset CAD where the strength of evidence for linkage was increased in families with higher mean low density lipoprotein-cholesterol (LDL-C). Therefore, we sought to fine-map the peak using association mapping of LDL-C as an intermediate disease-related trait to further define the etiology of this linkage peak. The study populations consisted of 1908 individuals from the CATHGEN biorepository of patients undergoing cardiac catheterization; 254 families (N = 827 individuals) from the GENECARD familial study of early-onset CAD; and 162 aorta samples harvested from deceased donors. Linkage disequilibrium-tagged SNPs were selected with an average of one SNP per 20 kb for 126.6-160.2 MB (region of highest linkage) and less dense spacing (one SNP per 50 kb) for the flanking regions (117.7-126.6 and 160.2-167.5 MB) and genotyped on all samples using a custom Illumina array. Association analysis of each SNP with LDL-C was performed using multivariable linear regression (CATHGEN) and the quantitative trait transmission disequilibrium test (QTDT; GENECARD). SNPs associated with the intermediate quantitative trait, LDL-C, were then assessed for association with CAD (i.e., a qualitative phenotype) using linkage and association in the presence of linkage (APL; GENECARD) and logistic regression (CATHGEN and aortas).
We identified four genes with SNPs that showed the strongest and most consistent associations with LDL-C and CAD: EBF1, PPP2R2B, SPOCK1, and PRELID2. The most significant results for association of SNPs with LDL-C were: EBF1, rs6865969, p = 0.01; PPP2R2B, rs2125443, p = 0.005; SPOCK1, rs17600115, p = 0.003; and PRELID2, rs10074645, p = 0.0002). The most significant results for CAD were EBF1, rs6865969, p = 0.007; PPP2R2B, rs7736604, p = 0.0003; SPOCK1, rs17170899, p = 0.004; and PRELID2, rs7713855, p = 0.003.
Using an intermediate disease-related quantitative trait of LDL-C we have identified four novel CAD genes, EBF1, PRELID2, SPOCK1, and PPP2R2B. These four genes should be further examined in future functional studies as candidate susceptibility loci for cardiovascular disease mediated through LDL-cholesterol pathways.
PMCID: PMC3309961  PMID: 22369142
Cardiovascular Disease; Positional Cloning; Intermediate Phenotype; Linkage; Fine Mapping

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