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e17026 Background: Androgen receptor (AR) signaling is a critical pathway in prostate cancer progression. Reactivation of the AR pathway is a key driver in mCRPC. Patients with mCRPC often develop resistance to novel AR signaling inhibitors (ARSIs) such as enzalutamide. AR inhibitor resistance leads to shorter overall and progression-free survival and can be attributed to AR gene amplification with subsequent AR overexpression and androgen-sensitization in prostate tumors. Identifying novel modulators of AR amplification in patients progressing on ARSIs may lead towards potential targets in drug discovery. Methods: In this cross-sectional study, an in silico patient model was developed on prescribed drug therapies and failed therapies patient information, PSA measures, ̃100 mutation variables including somatic, germline, and gain/loss mutations, and ̃1K gene expressions data from 275 mCRPC patients obtained from the Tempus database using GNS Healthcare’s Causal artificial intelligence technology, REFS. A causal network model was reconstructed based on patient data with inferred effect estimates. The network model was topologically surveyed for biological interactions. Results: Causal analysis of this model uncovered two germline mutations, located in PTCH1 and AXIN2, which modify the effect of AR copy number gain ( ARgain+ : copy number 6, ARgain- : copy number < 6) on AR gene expression. For PTCH1-mutant group, there was a 2-fold increase in AR gene expression in ARgain+ patients compared to ARgain- patients (p = 2.1e-12), while only 1.4 fold increase in AR gene expression from the PTCH1 non-mutant group (p = 6.3e-08). Similarly, there was a 2-fold increase in AR gene expression in ARgain+ patients compared to ARgain- patients (p = 7.2e-16) for the AXIN2-mutant group, while only one-fold increase in AR gene expression with the AXIN2 non-mutant group (p = 0.001). The C to T missense mutation in codon 3746 in PTCH1 and codon 148 in AXIN2 have higher prevalences, 55% and 72%, respectively in this mCRPC cohort compared to their population allele frequencies, 38% and 47%, respectively. Conclusions: PTCH1 and AXIN2 mutations from our analyses is consistent with a literature reported role for Hedgehog signaling and Wnt/-catenin signaling pathways, respectively, influencing the disease progression in castration-resistant prostate cancer. Our findings suggest that the missense germline mutations in PTCH1 and AXIN2 predicts response to enzalutamide and other ARSIs in CRPC setting, and propose potential targets for combination therapy to overcome ARSI drug resistance in hormone-refractory prostate cancer. [Table: see text]

Background: Indications for the primary prevention of sudden death using an implantable cardioverter defibrillator (ICD) are based predominantly on left ventricular ejection fraction (LVEF). However, right ventricular ejection fraction (RVEF) is also a known prognostic factor in a variety of structural heart diseases that predispose to sudden cardiac death. We sought to investigate the relationship between right and left ventricular parameters (function and volume) measured by cardiovascular magnetic resonance (CMR) among a broad spectrum of patients considered for an ICD. Methods: In this retrospective, single tertiary-care center study, consecutive patients considered for ICD implantation who were referred for LVEF assessment by CMR were included. Right and left ventricular function and volumes were measured. Results: In total, 102 patients (age 62±14 years; 23% women) had a mean LVEF of 28±11% and RVEF of 44±12%. The left ventricular and right ventricular end diastolic volume index was 140±42 mL/m2 and 81±27 mL/m2, respectively. Eighty-six (84%) patients had a LVEF

To examine the prognostic significance of low QRS voltage in a large contemporary cohort of patients with a broad spectrum of acute coronary syndromes (ACS).12409 patients with STEMI or NSTE-ACS from the Global Registry of Acute Coronary Events (GRACE) and Canadian ACS I registries were stratified based on the presence of low QRS voltage (0.5 mV in all limb leads and1.0 mV in all precordial leads) on the admission ECG. We performed multivariable logistic regression to assess the independent association between low voltage and in-hospital and 6-month mortality, and tested for its interaction with ST-segment deviation for these outcomes.Patients with low voltage (3.2%) had higher GRACE risk scores, rates of prior myocardial infarction, and pathological Q waves, with less prevalent ST-segment deviation and ST-segment depression. They had worse left ventricular function and higher unadjusted rates of in-hospital and 6-month mortality. After adjustment for established prognosticators in the GRACE risk models in multivariable analysis, low voltage was independently associated with higher in-hospital mortality (adjusted OR 1.77, 95% CI 1.13-2.78, P=0.013) and mortality/re-infarction (adjusted OR 1.42, 95% CI 1.05-1.93, P=0.023), but not 6-month mortality (adjusted OR 1.25, 95% CI 0.85-1.84, P=0.27). There was no significant interaction between low voltage and ST-segment deviation for any endpoint (interaction P0.10 for all endpoints).Low QRS voltage was associated with previous myocardial infarction and adverse hemodynamic variables at presentation. After adjusting for other prognosticators, low voltage independently predicted higher in-hospital mortality. This increased risk was not modulated by concomitant ST-segment deviation.

68 Background: Immune checkpoint inhibitors have achieved unprecedented success in several cancer types, yet only a subset of patients derives clinical benefit. Better understanding of tumor-immune interactions is imperative to improve clinical outcomes. Bayesian causal machine learning was applied on real world data to elucidate the molecular drivers of immune subtypes of tumors. Methods: Using a Reverse Engineering Forward Simulation (REFS) platform, ensembles of causal models were built on genomics, transcriptomics, and clinical data from 681 non-small cell lung carcinoma (NSCLC), 328 lung adeno (LUAD) and 353 lung squamous cell (LUSC), and 413 head and neck squamous cell carcinoma (HNSCC) patients from TCGA. The outcomes modeled were six tumor immune subtypes (Thorsson et al., 2018): wound-healing, IFNγ dominant, inflammatory, lymphocyte-depleted, immunologically quiet, and TGFβ dominant. Causal drivers of immune subtypes were identified from average causal effect (ACE) of the variables, as computed from the counterfactual simulations. ACE was defined as median of posterior distribution of odds ratio (1 vs 0 for discrete; 95th vs. 5th %ile for continuous variables). Results: The models showed impressive k-fold cross validation predictive performance (AUC ~ 0.8-0.9) for the most prevalent immune subtypes in TCGA: wound-healing and IFNg dominant in both LUAD and HNSCC, as well as inflammatory in LUAD. The potential causal drivers of the tumor immune subtypes and their ACE are listed in Table. The findings suggest that macrophage activation and polarization, which is driven in part by metabolic reprogramming, is a primary driver of tumor immune subtypes. Conclusions: Bayesian causal modeling revealed literature-supported hypotheses regarding predictors of response (CXCL13) and resistance (STK11 mutation, mTOR pathway) to PD-(L)1 blockade therapy. The additional target pathways such as AKT1/mTOR may be actionable for altering immunogenicity of tumors. [Table: see text]

Background The predictive value of ascending aortic distensibility (AAD) for mortality and hard cardiovascular disease (CVD) events has not been fully established. Objectives This study sought to assess the utility of AAD to predict mortality and incident CVD events beyond conventional risk factors in MESA (Multi-Ethnic Study of Atherosclerosis). Methods AAD was measured with magnetic resonance imaging at baseline in 3,675 MESA participants free of overt CVD. Cox proportional hazards regression was used to evaluate risk of death, heart failure (HF), and incident CVD in relation to AAD, CVD risk factors, indexes of subclinical atherosclerosis, and Framingham risk score. Results There were 246 deaths, 171 hard CVD events (myocardial infarction, resuscitated cardiac arrest, stroke and CV death), and 88 HF events over a median 8.5-year follow-up. Decreased AAD was associated with increased all-cause mortality with a hazard ratio (HR) for the first versus fifth quintile of AAD of 2.7 (p = 0.008) independent of age, sex, ethnicity, other CVD risk factors, and indexes of subclinical atherosclerosis. Overall, patients with the lowest AAD had an independent 2-fold higher risk of hard CVD events. Decreased AAD was associated with CV events in low to intermediate- CVD risk individuals with an HR for the first quintile of AAD of 5.3 (p = 0.03) as well as with incident HF but not after full adjustment. Conclusions Decreased proximal aorta distensibility significantly predicted all-cause mortality and hard CV events among individuals without overt CVD. AAD may help refine risk stratification, especially among asymptomatic, low- to intermediate-risk individuals.

While prior work has suggested that a high-grade atrioventricular block (HAVB) in the setting of an acute coronary syndrome (ACS) is associated with in-hospital death, limited information is available on the incidence of, and death associated with, HAVB in ACS patients receiving contemporary management.The incidence of HAVB was determined within The Global Registry of Acute Coronary Events (GRACE). The clinical characteristics, in-hospital therapies, and outcomes were compared between patients with and without HAVB. Factors associated with death in patients with HAVB were determined. A total of 59 229 patients with ACS between 1999 and 2007 were identified; 2.9% of patients had HAVB at any point during the index hospitalization; 22.7% of whom died in hospital [adjusted odds ratio (OR) = 4.2, 95% confidence interval (CI), 3.6-4.9, P0.001]. The association between HAVB and in-hospital death varied with type of ACS [OR: ST-segment elevation myocardial infarction (STEMI) = 3.0; non-STEMI = 6.4; unstable angina = 8.2, P for interaction0.001]. High-grade atrioventricular block present at the time of presentation to hospital (vs. occurring in-hospital) and early (12 h) percutaneous coronary intervention or fibrinolysis (vs.12 h or no intervention) were associated with improved in-hospital survival, whereas temporary pacemaker insertion was not. Patients with HAVB surviving to discharge had similar adjusted survival at 6 months compared with those without HAVB. A reduction in the rate of, but not in-hospital mortality associated with, HAVB was noted over the study period.Although the incidence of HAVB is low and decreasing, this complication continues to have a high risk of in-hospital death.

Limited longitudinal data are available on attainment of guideline-recommended treatment targets among ambulatory patients at high risk for cardiovascular events.The Vascular Protection registry and the Guidelines Oriented Approach to Lipid Lowering registry recruited 8056 ambulatory patients at high risk for, or with established cardiovascular disease; follow-up was not protocol-mandated. We stratified the study population according to the availability of 6-month follow-up data into 2 groups, and compared their clinical characteristics, medication profile, and attainment of contemporaneous guideline-recommended blood pressure (BP) and lipid targets both at enrollment and at 6-month follow-up.Of the 8056 patients, only 5371 (66.7%) patients had 6-month follow-up, who had significant increases in the use of statins and antihypertensive medications at 6 months compared with at enrollment (all P0.001). Compared with at time of enrollment, more patients attained the BP target (45.3% vs 42.3%), low-density lipoprotein cholesterol (LDL-C) target (62.8% vs 45.8%), and both targets (29.7% vs 21.6%) at 6-month follow-up (all P0.001). In multivariable analysis, independent predictors of attainment of BP target included history of coronary artery disease and heart failure (all P ≤ 0.001). On the other hand, advanced age, diabetes, coronary artery disease, previous coronary revascularization, and use of statin therapy were independently associated with achievement of LDL-C target (all P0.005).Most (50%) patients without 6-month follow-up did not attain guideline-recommended BP and LDL-C targets at enrollment. Although BP and lipid control improved at 6 months among patients with follow-up, most still failed to achieve optimal BP and lipid targets. Effective ongoing quality improvement measures and follow-up are warranted.

Hypertension is a well-established risk factor for cardiovascular disease, whereas low systolic blood pressure (SBP) is a powerful adverse prognosticator in acute coronary syndrome. However, it is unclear whether the prognostic significance of low SBP differs in patients with versus without prior history of hypertension. We sought to investigate the relationships between presenting SBP, prior hypertension, antihypertensive medication use, and outcomes in non-ST-segment elevation acute coronary syndrome (NSTEACS).Using data from GRACE/GRACE(2) and CANRACE, we stratified 10,337 patients with NSTEACS from 1999 to 2008 into 2 groups: those with and those without prior diagnosis of hypertension. We performed multivariable logistic regression analysis to assess the prognostic significance of prior hypertension on in-hospital mortality and tested for the interactions between prior hypertension, antihypertensive medication use, and presenting SBP.Compared with patients without prior hypertension (n = 3,732), those with prior hypertension (n = 6,605) were older; more likely to be female; and more frequently had diabetes, previous myocardial infarction, heart failure, renal insufficiency, and higher Killip class and GRACE risk scores on presentation. Patients with prior hypertension were more likely to be on antihypertensive medications before admission, to present with higher SBP, and to have heart failure or cardiogenic shock in hospital (6.0% vs 10.1%; P.001). In-hospital mortality was higher among patients presenting with lower SBP but did not differ between the groups with and without prior hypertension. In multivariable analysis, neither prior hypertension (adjusted odds ratio = 1.15, 95% CI 0.78-1.70, P = .48) nor the number of antihypertensive medications used (P for trend = .84) was independently associated with in-hospital mortality. In contrast, SBP was a strong independent predictor of in-hospital mortality (adjusted odds ratio = 1.21 per 10 mm Hg lower, 1.15-1.27, P.001). There was no significant interaction between SBP and prior hypertension (P for interaction = .62) or pre-admission antihypertensive medication use (P for interaction = .46) with respect to in-hospital mortality.Low SBP on presentation, but not prior hypertension, was independently associated with in-hospital mortality in NSTEACS. The powerful prognostic value of SBP is similar regardless of a history of hypertension or pre-admission antihypertensive medication use.

Despite the availability of several acute coronary syndrome (ACS) prognostic risk scores, there is no appropriate score for early-risk stratification at the time of the first medical contact with patients with ACS. The primary objective of this study is to develop a simple risk score that can be used for early-risk stratification of patients with ACS.We derived the risk score from the Acute Myocardial Infarction in Quebec and Canada ACS-1 registries and validated the risk score in 4 other large data sets of patients with ACS (Canada ACS-2 registry, Canada-GRACE, EFFECT-1, and the FAST-MI registries). The final risk score is named the Canada Acute Coronary Syndrome Risk Score (C-ACS) and ranged from 0 to 4, with 1 point assigned for the presence of each of these variables: age ≥75 years, Killip1, systolic blood pressure100 mm Hg, and heart rate100 beats/min. The primary end points were short-term (inhospital or 30-day) and long-term (1- or 5-year) all-cause mortality.The C-ACS has good predictive values for short- and long-term mortality of patients with ST-segment elevation myocardial infarction and non-ST-segment elevation ACS. The negative predictive value of a C-ACS score ≥1 is excellent at ≥98% (95% CI 0.97-0.99) for short-term mortality and ≥93% (95% CI 0.91-0.96) for long-term mortality. In other words, a C-ACS score of 0 can potentially identify correctly ≥97% short-term survivors and ≥91% long-term survivors.The C-ACS risk score permits rapid stratification of patients with ACS. Because this risk score is simple and easy to memorize and calculate, it can be rapidly applied by health care professionals without advanced medical training.

Aims Left ventricular (LV) circumferential strain (Ecc) is a sensitive index of regional myocardial function. Currently, no studies have assessed its prognostic value in general population. We sought to investigate whether Ecc has a prognostic value for predicting incident heart failure (HF) and other major cardiovascular events in asymptomatic individuals without a history of previous cardiovascular diseases. Methods and results We, prospectively, assessed incident HF and atherosclerotic events during a 5.5 ± 1.3-year period in 1768 asymptomatic individuals aged 45–84 (mean age 65 years; 47% female) who underwent tagged magnetic resonance imaging for strain determination. During the follow-up period, 39 (2.2%) participants experienced incident HF and 108 (6.1%) participants had atherosclerotic cardiovascular events. Average of peak Ecc of 12-LV segments (Ecc-global) and mid-slice (Ecc-mid) was −17.0 ± 2.4 and −17.5 ± 2.7%, respectively. Participants with average absolute Ecc-mid lower than −16.9% had a higher cumulative hazard of incident HF (log-rank test, P = 0.001). In cox regression analysis, Ecc-mid predicted incident HF independent of age, diabetes status, hypertension, interim myocardial infarction, LV mass index, and LV ejection fraction (hazard ratio 1.15 per 1%, 95% CI: 1.01–1.31, P = 0.03). This relationship remained significant after adjustment for LV-end-systolic wall stress into covariates. In addition, by adding Ecc-mid to risk factors, LV ejection fraction, and the LV mass index, both the global χ2 value (76.6 vs. 82.4, P = 0.04) and category-less net-reclassification index ( P = 0.01, SE = 0.18, z = 2.53) were augmented for predicting HF. Circumferential strain was also significantly related to the composite atherosclerotic cardiovascular events, but its relationship was attenuated after introducing the LV mass index. Conclusion Circumferential shortening provides robust, independent, and incremental predictive value for incident HF in asymptomatic subjects without any history of previous clinical cardiovascular disease. Clinical Trial Registration: . Unique identifier: [NCT00005487][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00005487&atom=%2Fehj%2Fearly%2F2013%2F05%2F03%2Feurheartj.eht133.atom

The early diagnosis of acute coronary syndrome (ACS) remains challenging, and a considerable proportion of patients are diagnosed with "possible" ACS on admission. The Global Registry of Acute Coronary Events (GRACE/GRACE(2)) and Canadian Registry of Acute Coronary Events (CANRACE) enrolled 16,618 Canadian patients with suspected ACS in 1999 to 2008. We compared the demographic and clinical characteristics, use of cardiac procedures, prognostic accuracy of the GRACE risk score, and in-hospital outcomes between patients given an admission diagnosis of "definite" versus "possible" ACS by the treating physician. Overall, 11,152 and 5,466 patients were given an initial diagnosis of "definite" ACS and "possible" ACS, respectively. Patients with a "possible" ACS had higher GRACE risk score (median 130 vs 125) and less frequently received aspirin, clopidogrel, heparin, or β blockers within the first 24 hours of presentation and assessment of left ventricular function, stress testing, cardiac catheterization, and percutaneous coronary intervention (all p

The TRANSFER-AMI study demonstrated that early routine percutaneous coronary intervention post-fibrinolysis (pharmacoinvasive strategy) is superior to conservative management for ST-elevation myocardial infarction. However, it is not clear whether treatment efficacy differs between men and women.In this pre-specified subgroup analysis, we compared the efficacy of a pharmacoinvasive strategy in men versus women with acute ST-elevation myocardial infarction who were randomized to a pharmacoinvasive versus standard management following fibrinolysis. The primary end point was a composite of death, recurrent myocardial infarction, recurrent ischemia, heart failure and shock at 30 days. We tested for treatment heterogeneity between men and women using the Breslow-Day test. We also performed multivariable analysis adjusting for GRACE risk score and its interaction with treatment assignment, and evaluated for death/recurrent myocardial reinfarction as a secondary outcome.Of the 1059 patients, 843 were men and 216 were women. Compared to men, women were older, had worse Killip class, higher GRACE risk score, and higher rates of death and death/myocardial reinfarction at 30 days. The primary end point did not differ significantly between men and women (13.4% vs 16.7%, P = .22). Compared to standard treatment, a pharmacoinvasive strategy was associated with a lower rate of the primary end point in men (17.5% vs 9.4%, respectively, P.001), but not in women (16.2% vs 17.1%, P = .86). There was a trend toward an interaction between treatment assignment and sex for the composite primary end point (P = .06). After adjustment for the significant interaction between GRACE risk score and treatment (P.001), there was no significant interaction between sex and treatment for all the end points (all P.40).The borderline heterogeneity in treatment efficacy of a pharmacoinvasive strategy in men versus women was no longer evident after adjustment for the difference in baseline risk. This suggests that sex per se was not an important determinant of the efficacy of a pharmacoinvasive strategy. Owing to the small number of women in this trial, further study in this area is needed.

Background Systemic inflammation has been linked to the development of heart failure in population studies including Multi-Ethnic Study of Atherosclerosis (MESA), but little evidence exists regarding potential mechanism of this relationship. In this study, we used longitudinal magnetic resonance imaging follow-up analysis to examine whether C-reactive protein (CRP) levels relate to progressive myocardial functional deterioration as a potential mechanism of incident heart failure. Methods Regional myocardial functional data from MESA participants who had baseline CRP measurement and also underwent tagged cardiac magnetic resonance imaging both at baseline and at 5-year follow-up were analyzed. Left ventricular midwall and midslice peak circumferential strain (Ecc), of which a more negative value denotes stronger regional myocardial function, was measured. Circumferential strain change was calculated as the difference between baseline and follow-up Ecc. Results During the follow-up period, participants (n = 785) with elevated CRP experienced a decrease in strain, independent of age, gender, and ethnicity (B = 0.081, ΔEcc change per 1 mg/L CRP change, 95% CI 0.036-0.126, P b .001, model 1) and, additionally, beyond systolic blood pressure, heart rate, diabetes, smoking status, body mass index, current medication, and glomerular filtration rate (B = 0.099, 0.052-0.145, P b .001, model 2). The relationship remained statistically significant after further adjustment for left ventricular mass, coronary calcium score, and interim clinical coronary events (B = 0.098, 0.049-0.147, P b .001, model 3). Conclusion Higher CRP levels are related to progressive myocardial functional deterioration independent of subclinical atherosclerosis and clinical coronary events in asymptomatic individuals without previous history of heart disease. (Am Heart J

Background The prognostic impact of atrial fibrillation (AF) in the setting of acute coronary syndrome (ACS) is controversial. Furthermore, there are limited real-world data on the management of ACS patients with history of AF. Methods The Global Registry of Acute Coronary Events (GRACE/GRACE2) and Canadian Registry of Acute Coronary Events (CANRACE) enrolled 14,285 patients across Canada between 1999 and 2008. Patients were stratified by the presence of history of AF. We compared clinical characteristics, medical therapies, cardiac procedures, and clinical outcomes between the 2 groups. Results Overall, 1333 of the enrolled patients (9.3%) had history of AF, of whom 51.5% presented with non–ST-segment elevation myocardial infarction, 29.5% with unstable angina, and 19.1% with ST-segment elevation myocardial infarction. Compared with the group without, patients with a history of AF less frequently received evidence-based antiplatelet and antithrombin therapies, left ventricle ejection fraction assessment, and coronary angiography (all P 0.001); they also had higher unadjusted rates of in-hospital death, myocardial (re)infarction, and heart failure. However, in multivariable analysis, history of AF was not found to be independently associated with in-hospital mortality (adjusted odds ratio [OR] = 1.12; 95% confidence interval (CI), 0.73-1.73; P = 0.61) or death and/or myocardial reinfarction (adjusted OR=1.15; 95% CI, 0.87-1.5; P = 0.34). Conclusions History of AF is common among ACS patients. They received less evidence-based medical and invasive therapies than ACS patients without history of AF. History of AF is a negative independent predictor of in-hospital coronary angiography but was not found to be independently associated with adverse outcomes.

The question of whether gender-related disparities still exist in the treatment and outcomes of patients presenting with acute coronary syndromes (ACS) remains controversial. Using data from 4 registries spanning a decade, we sought to determine whether sex-related differences have persisted over time and to examine the treating physician's rationale for adopting a conservative management strategy in women compared with men.From 1999 to 2008, 14,196 Canadian patients with non-ST-segment elevation ACS were recruited into the Acute Coronary Syndrome I (ACSI), ACSII, Global Registry of Acute Coronary Events (GRACE/GRACE(2)), and Canadian Registry of Acute Coronary Events (CANRACE) prospective multicenter registries.Women in the study population were found to be significantly older than men and were more likely to have a history of heart failure, diabetes, or hypertension. Fewer women were treated with thienopyridines, heparin, and glycoprotein IIb/IIIa inhibitors compared with men in GRACE and CANRACE. Female gender was independently associated with a lower in-hospital use of coronary angiography (adjusted odds ratio 0.76, 95% CI 0.69-0.84, P.001) and higher in-hospital mortality (adjusted odds ratio 1.26, 95% CI 1.02-1.56, P = .036), irrespective of age (P for interaction =.76). Underestimation of patient risk was the most common reason for not pursuing an invasive strategy in both men and women.Despite temporal increases in the use of invasive cardiac procedures, women with ACS are still more likely to be treated conservatively, which may be due to underestimation of patient risk. Furthermore, they have worse in-hospital outcomes. Greater awareness of this paradox may assist in bridging the gap between current guidelines and management practices.

Background We examine the clinical characteristics and outcomes of ST-elevation myocardial infarction (STEMI) patients receiving various reperfusion therapies in 2 contemporary Canadian registries. Methods Of 4045 STEMI patients, 2024 received reperfusion therapy and had complete data on invasive management. They were stratified by reperfusion strategy used: primary percutaneous coronary intervention (PCI) (n =716); fibrinolysis with rescue PCI (n =177); fibrinolysis with urgent/elective PCI (n =210); and fibrinolysis without PCI (n =921). Data were collected on clinical and laboratory findings, and outcomes. Results Compared with fibrinolytic-treated patients, patients treated with primary PCI were younger and had higher Killip class, had longer time to delivery of reperfusion therapy, and utilized more antiplatelet therapy but less heparin, β-blockers and angiotensin-converting enzyme inhibitors. In-hospital death occurred in 2.7% of patients treated with primary PCI, 1.7% fibrinolysis-rescue PCI, 1.0% fibrinolysis-urgent/elective PCI, and 4.8% fibrinolysis-alone ( P =0.009); the rates of death/reinfarction were 3.9%, 4.0%, 4.3%, and 7.1% ( P =0.032), respectively. The rate of shock was highest in the primary PCI group. Rates of heart failure or major bleeding were similar in the 4 groups. In multivariable analysis, no PCI during hospitalization was associated with death and reinfarction (adjusted odds ratio=1.66; 95% confidence interval, 1.03-2.70; P =0.04). Conclusions Clinical features, time to reperfusion, and medication utilization differed with respect to the reperfusion strategy. While low rates of re-infarction/death were observed, these complications occurred more frequently in those who did not undergo PCI during index hospitalization.

Background Randomized trials have established the efficacy of clopidogrel in acute coronary syndromes (ACS). The benefit of clopidogrel has also been observed in the subgroup of ACS patients who subsequently undergo coronary artery bypass surgery (CABG); however, this therapy is discontinued preoperatively and the frequency with which clopidogrel is restarted post-CABG is unknown. Methods We examined the pattern of clopidogrel use in the Canadian Global Registry of Acute Coronary Events (GRACE), GRACE2, and CANRACE (2003-2008) post-CABG ACS patients. We stratified the patients according to whether they underwent CABG during their index hospitalization for ACS and whether they were prescribed clopidogrel at discharge. Results Among those patients in whom clopidogrel status at discharge was known, 5904 (60%) of 9841 were discharged from hospital on clopidogrel. Use of clopidogrel at discharge was observed in 2222 (40.8%) of 5443 patients who were medically managed (ie, did not undergo percutaneous coronary intervention [PCI] or CABG) and in 3585 (90.1%) of 3980 patients who underwent in-hospital PCI. Overall, 455 (3.3%) of 13,776 patients underwent CABG during the index hospitalization; 255 (56%) patients were started on clopidogrel during the first 24 hours, and 66 of these patients (25.9%) were discharged on clopidogrel. In contrast, 5681 (61.3%) of the 9262 patients who did not undergo in-hospital CABG were discharged on clopidogrel. Conclusions Although current guidelines recommend the use of clopidogrel post-CABG in patients with ACS, our observations suggest that only 1 in 4 or 5 Canadian patients are discharged on this therapy.

Objectives We sought to examine the prognostic value of subclinical left ventricular (LV) regional myocardial dysfunction (RMD) measured by magnetic resonance imaging (MRI) among asymptomatic individuals. Background LV RMD, defined as segmental impairment in systolic wall thickening, predicts adverse events in patients with established cardiovascular disease. MRI is highly accurate for detecting subtle RMD, of which the prognostic significance in a large multiethnic asymptomatic population is not known. Methods We used MRI to evaluate baseline regional LV myocardial function and prospectively followed a multiethnic (African American, Caucasian, Chinese, and Hispanic) population-based sample of 4,510 men and women without cardiovascular disease for a mean of 4.6 years. Regional myocardial dysfunction was defined as the presence of impaired systolic wall thickening ( Results Baseline prevalence of RMD was 25.6%. Heart failure developed in 34 (1.0%) and 30 (2.6%) participants without and with RMD, respectively (p Conclusions Among an asymptomatic multiethnic American cohort, RMD is an independent predictor beyond traditional risk factors and global LV assessment for incident heart failure and atherosclerotic cardiovascular events. The clinical utility of early recognition of this subclinical phenotype deserves further investigation. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487)

A 71-year-old asymptomatic woman is found to have an incidental cardiac mass on transthoracic echocardiography. Cardiac magnetic resonance (CMR) findings are consistent with lipotamous hypertrophy of the inter-atrial septum. Given the characteristic appearances on CMR, biopsy or surgery was not indicated and the patient was managed conservatively.

Anemia has been associated with adverse outcomes in patients with acute coronary syndromes (ACS). However, the underlying pathophysiologic mechanisms have not been well elucidated. We sought to determine the independent relation between the hemoglobin level and recurrent ischemia in patients with non-ST-segment elevation ACS using continuous electrocardiographic monitoring. In the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial, 746 patients presenting with non-ST-segment elevation ACS underwent continuous ST-segment monitoring for 48 hours. The data were analyzed independently at a core laboratory. We stratified the study population according to their hemoglobin level on presentation. The primary outcome of the study was recurrent ischemia, defined as ST-segment shifts on continuous electrocardiographic monitoring. Of the 705 patients with analyzable data, 64 had a baseline hemoglobin level120 g/L, 259 had a level of 120 to 139 g/L, 315 had a level of 140 to 159 g/L, and 67 had a level160 g/L. The corresponding rates of recurrent ischemia were 39.1%, 22.0%, 15.6%, and 11.9% (p for trend0.001). A lower hemoglobin level was associated with advanced age, co-morbidities, and a higher GRACE risk score. In multivariable analysis adjusting for these confounders, lower hemoglobin levels retained a significant independent association with recurrent ischemia (p for trend = 0.004). In conclusion, a lower hemoglobin level at presentation was independently associated with recurrent ischemia detected by continuous electrocardiographic monitoring in the setting of non-ST-segment elevation ACS. This suggests that anemia might predispose patients to recurrent ischemia, which could be an important underlying mediator of worse outcomes in patients with lower hemoglobin levels.

Obesity is associated with hypertension, dyslipidemia, and diabetes, but it is also an independent cardiovascular risk factor. We sought to evaluate the differences in treatment patterns and attainment of guideline-recommended targets among high-risk vascular outpatients in relation to their body mass index (BMI). The prospective Vascular Protection and Guideline Orientated Approach to Lipid Lowering Registries recruited 7,357 high-risk vascular outpatients in Canada from 2001 to 2004. We stratified the patient population into 3 groups according to their BMI: normal weight (BMI24.9 kg/m²), overweight (BMI 25 to 29.9 kg/m²), and obese (BMI30 kg/m²). We evaluated the rates of attainment for contemporary guideline targets of blood pressure (140/90 or130/80 mm Hg in the presence of diabetes) and lipids (low-density lipoprotein [LDL]2.5 mmol/L [96.7 mg/dl] and total cholesterol [TC]/high-density lipoprotein [HDL] ratio4.0). Of the 7,357 patients, 1,305 (17.7%) were normal weight, 2,791 (37.9%) overweight, and 3,261 (44.4%) obese, as determined by the BMI. Obese patients were younger and more likely to have hypertension and diabetes (all p0.001 for trend). Obese patients had higher baseline blood pressure, TC, LDL cholesterol, triglyceride levels and TC/HDL ratio, and lower HDL cholesterol. Obese patients were more likely to be treated with antihypertensive agents (p = 0.002), angiotensin-converting enzyme inhibitors (p = 0.024), angiotensin receptor blockers (p0.001), and high-dose statin therapy (p = 0.001). On multivariable analyses, obese patients were less likely to attain the blood pressure (odds ratio 0.77, 95% confidence interval 0.66 to 0.90, p = 0.001) and TC/HDL ratio (odds ratio 0.48, 95% confidence interval 0.42 to 0.55, p0.001) targets but not the LDL targets (odds ratio 0.89, 95% confidence interval 0.78 to 1.03, p = 0.11). In conclusion, only a minority ambulatory patients at high cardiovascular risk achieved both guideline-recommended blood pressure and lipid targets, and this significant treatment gap was more pronounced among obese patients. Our findings underscore the opportunity to optimize the treatment of these high-risk patients.

Background— Acute coronary syndrome (ACS) patients in the highest risk categories are least likely to receive evidence-based treatments (EBTs). We sought to determine why physicians do not prescribe EBTs for patients with non–ST-segment–elevation ACSs and the factors determining use of these treatments after 1 year. Methods and Results— One thousand nine hundred fifty-six non–ST-segment-elevation ACS patients were enrolled in the prospective, multicenter Canadian ACS registry II between October 2002 and December 2003. Each patient's physician gave reasons why guideline-indicated medication(s) was not prescribed during hospitalization. Medication use and reason(s) for discontinuation after 1 year were obtained by telephone interview of the patients. The commonest reason for not prescribing EBTs was “not high-enough risk” or “no evidence/guidelines to support use.” However, Global Registry of Acute Coronary Events scores of patients not treated for this reason were often similar to or higher than those of patients prescribed such treatment. After 1 year, 77% of patients not on optimal ACS treatment at discharge remained without optimal treatment, and overall antiplatelet, β-blocker, and angiotensin-converting enzyme inhibitor use declined. Approximately one third of patients not taking EBTs had stopped their medication without instruction from their doctor. Conclusions— Nonprovision of EBTs may be due to subjective underestimation of patient risk and hence, likely treatment benefit. Oversights in care delivery were also apparent. Objective risk stratification, combined with efforts to ensure provision and adherence to EBTs, should be encouraged.

Although randomized controlled trials support the use of intensive medical and invasive therapies for non-ST segment elevation acute coronary syndromes (NSTE-ACS), major bleeding is a serious treatment complication. We sought to determine the temporal trend of in-hospital major bleeding among patients with NSTE-ACS, in relation to the evolving management pattern.We identified 14 111 NSTE-ACS patients enrolled in 4 successive, prospective, multicenter registries (ACS I, 1999-2001; ACS II, 2002-2003; GRACE, 2004-2007; and CANRACE, 2008) in Canada between 1999 and 2008. We collected data on patient characteristics, use of cardiac medications and procedures on standardized case report forms. In all registries, major bleeding was defined a priori as life threatening or fatal bleeding, bleeding requiring transfusion of ≥2 U of packed red cells, or resulting in an absolute decrease in hemoglobin of30g/L.A total of 14 111 patients had a final diagnosis of NSTE-ACS and were included in this study (3294 in the ACS-I registry, 1956 in the ACS-II registry, 7543 in GRACE, and 1318 in CANRACE). Over time, there was a substantial increase in the use of dual anti-platelet (aspirin and thienopyridine) therapy (P for trend.001), and in rates of in-hospital cardiac catheterization and percutaneous coronary intervention (both Ps for trend.001). Overall, major bleeding was relatively infrequent (1.7%). There was no significant increase in the unadjusted rates of major bleeding over time (P for trend = .19). In multivariable analysis adjusting for GRACE risk score and intensive treatment, enrolment period was not an independent predictor of bleeding (P for trend = .98). There was no interaction between the enrolment period and the use of intensive medical and invasive management.Despite more widespread use of dual anti-platelet therapies and invasive cardiac procedures in the management of NSTE-ACS, the rate of major bleeding remains relatively low and has not increased significantly over time. Our findings suggest that physicians selectively target treatment for their patients, and these evidence-based therapies can be safely administered to ACS patients in clinical practice.

QRS prolongation with or without bundle branch block (BBB) has been associated with adverse outcome in myocardial infarction; we examined the relationship between QRS duration and outcome in a broad spectrum of patients with acute coronary syndrome (ACS).Core laboratory evaluation of the presenting electrocardiogram in Canadian ACS Registry patients (n = 5,003) showed 4,289 (85.7%) had QRS120 milliseconds, 202 (4.0%) patients had QRSor =120 milliseconds without BBB, 262 (5.2%) had left BBB (LBBB), and 250 (5.0%) had right BBB. Compared to patients with QRS120 milliseconds, patients with QRSor =120 milliseconds without BBB had higher in-hospital (3.5% vs 1.9%, odds ratio [OR] 1.87, 95% CI 0.85-4.09, P = .12) and 1-year mortality (14.9% vs 7.7%, OR 2.10, 95% CI 1.38-3.18, P = .001). In-hospital and 1-year mortality was significantly higher in patients with BBB (eg, LBBB compared with QRS120 milliseconds) (5.0% vs 1.9%, OR 2.71, 95% CI 1.49-4.94, P = .001, and 23.8% vs 7.7%, OR 3.74, 95% CI 2.72-5.13, P.001). Analyzed as a continuous variable and after adjustment for validated prognosticators, QRS duration was an independent predictor of 1-year death (OR 1.11, 95% CI 1.06-1.16, P.001) and death/myocardial infarction (OR 1.06, 95% CI 1.02-1.11, P = .003). However, when using clinically applicable QRS duration evaluation, only LBBB was an independent predictor of 1-year mortality (OR 1.93, 95% CI 1.28-2.90, P = .002).In patients presenting with a broad spectrum of suspected ACS, QRS prolongation-particularly in the setting of LBBB-is an independent predictor of in-hospital and 1-year mortality.

In-hospital assessment of left ventricular ejection fraction (LVEF) in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is emphasized in current practice guidelines. There are limited data regarding the evaluation of LVEF and clinical characteristics and in-hospital management in the "real world."Registries including the Canadian Acute Coronary Syndrome (ACS) I and II, Global Registry of Acute Coronary Events (main GRACE/expanded GRACE(2)), and Canadian Registry of Acute Coronary Events (CANRACE) enrolled 13,703 NSTE-ACS patients across Canada between 1999 and 2008. Patients were stratified by in-hospital LVEF measurement, and LVEF was categorized as normal, mildly, or moderately to severely impaired. We compared clinical characteristics, cardiac procedures, and clinical outcomes across these groups. Multivariable logistic regression identified factors independently associated with the assessment of LVEF.Overall, 8,116 patients (59.2%) had LVEF measurement, and of the 7,667 patients with available LVEF data, 4,470 (58.3%) had normal, 1,916 (25%) mildly impaired, and 1,281 (16.7%) moderately to severely impaired LVEF. Patients with LVEF assessment more frequently (all P.001) underwent cardiac catheterization, percutaneous coronary intervention or coronary bypass surgery, and had higher (both P.001) rates of myocardial (re) infarction and heart failure. In-hospital reinfarction, higher Killip class, abnormal biomarker, hospital stay10 days, and on-site cardiac catheterization facility were independently associated with LVEF assessment. Despite increasing LVEF assessment over time (P for trend.001), 31.2% of patients in the most recent registry (2008) had no in-hospital LVEF assessment.In-hospital LVEF assessment is not performed in many NSTE-ACS patients. The LVEF assessment, associated with increased use of evidence-based therapies and invasive cardiac procedures, was obtained more frequently in patients with myocardial (re) infarction, heart failure on presentation, and prolonged hospital stay.

The Global Registry of Acute Coronary Event (GRACE) risk score was developed in a large multinational registry to predict in-hospital mortality across the broad spectrum of acute coronary syndromes (ACS). Because of the substantial regional variation and temporal changes in patient characteristics and management patterns, we sought to validate this risk score in a contemporary Canadian population with ACS.The main GRACE and GRACE(2) registries are prospective, multicenter, observational studies of patients with ACS (June 1999 to December 2007). For each patient, we calculated the GRACE risk score and evaluated its discrimination and calibration by the c statistic and the Hosmer-Lemeshow goodness-of-fit test, respectively. To assess the impact of temporal changes in management on the GRACE risk score performance, we evaluated its discrimination and calibration after stratifying the study population into prespecified subgroups according to enrollment period, type of ACS, and whether the patient underwent coronary angiography or revascularization during index hospitalization.A total of 12,242 Canadian patients with ACS were included; the median GRACE risk score was 127 (25th and 75th percentiles were 103 and 157, respectively). Overall, the GRACE risk score demonstrated excellent discrimination (c statistic 0.84, 95% CI 0.82-0.86, P.001) for in-hospital mortality. Similar results were seen in all the subgroups (all c statistics/=0.8). However, calibration was suboptimal overall (Hosmer-Lemeshow P = .06) and in various subgroups.GRACE risk score is a valid and powerful predictor of adverse outcomes across the wide range of Canadian patients with ACS. Its excellent discrimination is maintained despite advances in management over time and is evident in all patient subgroups. However, the predicted probability of in-hospital mortality may require recalibration in the specific health care setting and with advancements in treatment.

Randomized controlled trials support the use of an early invasive strategy in high-risk patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). Although risk increases with age, limited data are available to support this strategy in older patients. The aims of this study were to examine temporal trends in the management and outcomes of NSTE ACS in elderly patients and to explore reasons for the lower use of early angiography in the aged population. Data from 11,732 patients with NSTE ACS were collected from 3 consecutive Canadian registries (ACS I, ACS II, and Global Registry of Acute Coronary Events [GRACE]/GRACE2) from 1999 to 2007. Rates of in-hospital cardiac catheterization, revascularization, infarction or reinfarction, and death were stratified by age (65, 65 to 74, andor = 75 years). Although overall, rates of in-hospital catheterization and revascularization increased over time (p0.001), the largest increase occurred in patients aged65 years. The strongest independent negative predictor of the use of cardiac catheterization was ageor = 75 years (adjusted odds ratio 0.45, 95% confidence interval 0.37 to 0.56, p0.001). Use of an early invasive approach was associated with a reduction in 1-year mortality across all age groups, but the absolute difference was greatest in patients agedor = 75 years. The underestimation of risk by physicians (ascertained in ACS II) was the most common reason for choosing a conservative strategy. In conclusion, despite an overall increased use of an early invasive strategy, elderly patients with NSTE ACS remain significantly less likely to undergo cardiac catheterization and revascularization and are often erroneously perceived to be at low risk by their physicians. Future studies should determine whether more aggressive treatment of these high-risk elderly patients improves outcomes.

This aim of this study was to assess the clinical utility of quantitative ST-segment depression (STD) for refining the risk stratification of non-ST elevation acute coronary syndromes in the prospective, multinational Global Registry of Acute Coronary Events (GRACE). Quantitative measurements of STD on admission electrocardiograms were evaluated independently by a core laboratory, and their predictive value for in-hospital and cumulative 6-month mortality was examined. Although more severe STD is a marker of increased short- and long-term mortality, it is also associated with higher risk clinical features and biomarkers. Thus, after adjustment for these clinically important predictors, quantitative STD does not provide incremental prognostic value beyond simple dichotomous evaluation for the presence of STD. Furthermore, adopting quantitative instead of the prognostically proven qualitative evaluation of STD does not improve risk discrimination afforded by the validated GRACE risk models. In conclusion, the findings do not support the quantification of STD in routine clinical practice beyond simple evaluation for the presence of STD as an integral part of comprehensive risk stratification using the GRACE risk score.

Background: Both neurohormonal derangements and alterations in the myocardial extracellular matrix are thought to contribute to adverse ventricular remodelling that results in worsening heart failure (HF). There is also emerging preclinical information to suggest that these signalling pathways mutually regulate in HF. Aim: To assess the relationships between plasma levels of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinase (TIMP), and neurohormonal profiles in chronic HF. Methods and results: In this substudy of 184 HF patients enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, plasma norepinephrine and epinephrine were measured with HPLC; atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), angiotensin II, aldosterone, and endothelin-1 were measured with immunoassays; MMP-2, MMP-9, and TIMP-1 were measured with 2-site sandwich ELISA assays. We used Spearman's rank correlation to examine the relationships between plasma MMP and neurohormone levels. Circulating ANP, BNP, and endothelin-1 levels were positively correlated with MMP-2 and TIMP-1 levels. Plasma level of aldosterone showed a weak positive correlation with MMP-9, but there was no significant correlation between angiotensin II, epinephrine or norepinephrine and MMP-2, MMP-9, or TIMP-1. Conclusions: These findings suggest that specific neurohormones and extracellular matrix modulators may play a coordinated role in the pathogenesis of HF.

Objective To assess the relationship between the evolution of T wave inversion (TWI) on the 24–48 h postadmission ECG and the patient characteristics, management and clinical outcomes among those with non-ST elevation acute coronary syndrome (NSTE-ACS). Methods We evaluated admission and 24–48 h follow-up ECGs of 7201 patients with NSTE-ACS from the prospective, multicentre Global Registry of Acute Coronary Events (GRACE) and Canadian ACS Registry I. We performed multivariable analyses to determine the association between new TWI (on follow-up ECG only), resolved TWI (on admission ECG only) and persistent TWI (on both admission and follow-up ECG) and inhospital and cumulative 6-month all-cause mortality. Results Patients with TWI were older, more likely to have cardiovascular risk factors, higher Killip class and GRACE risk scores. After adjustment for known prognostic factors, compared with patients presenting without TWI, new TWI was associated with significantly lower inhospital mortality (OR=0.60, 95% CI 0.38 to 0.95, p=0.029), whereas resolved (OR=1.06, 95% CI 0.65 to 1.75, p=0.81) and persistent (OR=0.73, 95% CI 0.48 to 1.11, p=0.14) TWI did not predict inhospital mortality. No TWI pattern independently predicted inhospital adverse cardiovascular events or cumulative 6-month mortality. In contrast, ST depression on the admission and follow-up ECG were independent predictors of inhospital and 6-month mortality. Conclusions Across the spectrum of NSTE-ACS, TWI within 48 h of presentation was associated with high-risk clinical features, but its presence or dynamic change did not provide additional prognostic value beyond other established clinical predictors.

Diabetes-related differences in treatment and clinical outcome of patients across the entire spectrum of acute coronary syndromes (ACSs) have potential clinical implications but have not been well studied.The multicenter, prospective, Canadian ACS Registry enrolled 4578 patients hospitalized for ACS between 1999 and 2001 across 9 provinces in Canada. We compared baseline characteristics, in-hospital and post-discharge treatments, and clinical outcome of diabetic and non-diabetic patients. The impact of diabetes on use of thrombolytic therapy and coronary revascularization; and the independent association between diabetes, treatments, and diabetes-treatment interactions on outcome were examined.Diabetic patients with ACS had more cardiovascular risk factors and higher-risk clinical presentation. They paradoxically received less evidence-based medications in-hospital, at discharge, and at 1-year. Although diabetes independently predicted higher 1-year mortality (OR 1.47, 95% CI 1.15-1.87; P = .002) after adjustment for validated prognosticators, it was also an independent predictor of not receiving thrombolytic therapy (OR 0.72, 95% CI 0.54-0.95; P = .021) and coronary revascularization (OR 0.69, 95% CI 0.59-0.82; P.001). These underused therapies were all independently associated with reduced 1-year mortality, with no significant diabetes-related treatment-outcome heterogeneity. Importantly, diabetes remained an independent adverse prognosticator even after further adjustment for these differences in treatment.Evidence-based therapies are underused in the contemporary management of diabetic patients with ACS, which partly explains their worse outcome. Diabetes should be considered a high-risk feature in ACS risk stratification that encourages more intensive treatments. Continued efforts to promote adherence to existing proven therapies and to develop novel treatment strategies targeting diabetes-specific cardiovascular pathophysiology are imperative to improve their adverse prognosis.

Matrix metalloproteinases (MMPs) can alter myocardial extracellular matrix and thereby contribute to adverse ventricular remodeling in progressive heart failure (HF). We hypothesized that increased plasma MMP levels correlate with increased left ventricular (LV) volumes and reduced LV ejection fraction (LVEF) in patients with HF.In the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, patients with symptomatic HF and LVEF0.40 were randomized to receive various combinations of therapies with candesartan, enalapril, and metoprolol CR. Left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and LVEF were determined by radionuclide angiography at baseline and at Week 43. Baseline and Week 43 plasma MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in 184 patients in this substudy. At baseline, plasma MMP-9 correlated positively with ESV (Spearman's rank correlation coefficient rho = 0.17, P = .02) and negatively with LVEF (rho = -0.18, P = .01). After 43 weeks, LVEF, EDV, and ESV increased significantly (all P.01); MMP-2 level increased (P = .01), but MMP-9 and TIMP-1 levels did not change significantly overall in the study population. Temporal changes in MMP-9 level were inversely correlated with changes in LVEF (rho = -0.16, P = .04). In multivariable analysis adjusting for clinical characteristics and treatment, a smaller proportional change in MMP-9 level after 43 weeks (below versus above median) predicted a concurrent improvement in LVEF (odds ratio = 2.35, 95% CI 1.24-4.46; P.01). Similar relationships for MMP-2 and TIMP-1 were not observed.Elevated plasma MMP-9 levels correlated with lower LVEF and higher ESV, whereas increasing MMP-9 levels are associated with a concurrent deterioration of LV function. These findings suggest that monitoring of plasma markers of myocardial matrix remodeling may provide important prognostic information with respect to ongoing adverse LV remodeling in HF patients.

It is unclear whether quantitative ST-segment assessment can improve risk stratification of unselected acute coronary syndrome (ACS) patients using the validated Global Registry of Acute Cardiac Events (GRACE) risk model.In the prospective, multicenter, Canadian ACS Registry, the admission electrocardiogram was evaluated centrally at a blinded core laboratory. Patients with ST-elevation myocardial infarction and other electrocardiogram confounders were excluded. ST depression (ST down) was measured and summed in all leads except aVR. Patients with ST down were divided into 3 groups based on tertiles of cumulative ST down. A multivariable model was developed to examine the independent prognostic value of ST down severity after adjusting for other known prognosticators in the GRACE risk model.Among 2590 patients with non-ST-elevation ACS, more severe ST down was associated with advanced age, higher heart rate and Killip class, elevated creatinine, abnormal biomarkers, higher GRACE risk score, and higher 1-year mortality (all P.001). After adjusting for these confounding prognosticators, the presence of any ST down remained independently associated with higher 1-year mortality (odds ratio 1.78, 95% CI 1.21-2.63, P = .004). However, the gradient of risk with increasing magnitude of ST down was no longer evident (adjusted odds ratios 1.77, 1.77, 1.81, for ascending tertiles of cumulative ST down, respectively). Moreover, quantitative ST down did not improve the model discrimination for 1-year mortality. The results were similar when the number of leads with ST down or the maximum magnitude of ST down was analyzed, after adjusting for tertiles of GRACE risk score or inhospital revascularization, or using the composite end point of death or myocardial (re)infarction at 1 year.Greater ST down is associated with other adverse prognosticators across the broad spectrum of non-ST-elevation ACS. Although the presence of any ST down is an independent predictor of 1-year mortality, its quantitative assessment is not as important as its mere presence when studied on the background of comprehensive clinical and biomarker evaluation in a nonclinical trial-based ACS population.

Our objective was to evaluate treatment patterns and the attainment of current National Cholesterol Education Program (NCEP)-recommended lipid targets in unselected high-risk ambulatory patients.Between December 2001 and December 2004, the prospective Vascular Protection and Guidelines Oriented Approach to Lipid Lowering Registries recruited 8056 outpatients with diabetes, established cardiovascular disease (CVD), or both, who had a complete lipid profile measured within 6 months before enrollment. The primary outcome measure was treatment success, defined as the achievement of LDL-cholesterol2.6 mmol/L (100 mg/dL) according to NCEP guidelines. We examined patient characteristics and use of lipid-modifying therapy in relation to treatment outcome, which included the recently proposed optional LDL-cholesterol target (1.8 mmol/L [70 mg/dL]) for very high-risk patients.Overall, 78.2% of patients were treated with a statin and 51.2% had achieved the recommended LDL-cholesterol target. Treatment success rate was highest in diabetic patients with CVD (59.6%), followed by nondiabetic patients with CVD (51.8%), and lowest (44.8%) in diabetic patients without CVD (P.0001). Compared with untreated patients, those on statins were more likely to achieve target (34.4% vs 55.9%, P.0001). Of the patients who failed to meet target, only 9.9% were taking high-dose statin, while 29.3% were not prescribed any statin therapy. Among very high-risk patients, 20.8% attained the optional LDL-cholesterol goal. In multivariable analysis, advanced age, male sex, diabetes, coronary artery disease, coronary revascularization, and use of statin were associated with treatment success (all P.0001).Despite the well-established benefits of available lipid-modifying drugs, current management of dyslipidemia continues to be suboptimal, with a substantial proportion of patients failing to achieve guideline-recommended lipid targets. There remains an important opportunity to improve the quality of care for these high-risk patients.

There are limited data on the treatment and long-term outcome of patients with renal dysfunction across the broad spectrum of acute coronary syndromes (ACS) in Canada.To examine the treatment patterns and outcome of ACS patients with renal dysfunction.In the prospective, multicentre, Canadian ACS Registry, 3510 patients hospitalized for ACS (including unstable angina, ST and non-ST elevation myocardial infarction) were categorized into four groups: normal renal function (creatinine clearance [CrCl] 90 mL/min or greater; n=1152), mild renal dysfunction (CrCl 60 mL/min to 89 mL/min; n=1253), moderate renal dysfunction (CrCl 30 mL/min to 59 mL/min; n=944) and severe renal dysfunction (CrCl less than 30 mL/min; n=161). Multivariable logistic regression analysis was performed to examine the independent prognostic value of renal dysfunction, and the association of various therapies with one-year survival.All-cause mortality at one year was 2.8%, 6.4%, 14.5% and 40.9% in patients with normal renal function, and mild, moderate and severe renal dysfunction, respectively (P for trend0.001). After adjusting for other prognosticators, moderate (OR 1.82, 95% CI 1.08 to 3.08) and severe (OR 6.29, 95% CI 3.37 to 11.77) renal dysfunction remained independent predictors of one-year death. Patients with renal dysfunction were less likely to receive fibrinolytic therapy, to undergo coronary angiography and revascularization in hospital, and to be treated with acetylsalicylic acid, beta-blockers and lipid-lowering therapy at discharge and at one-year follow-up. The association of in-hospital revascularization, and discharge use of acetylsalicylic acid and beta-blockers with better one-year survival was similar among patients with normal and impaired renal function.Renal dysfunction is prevalent and independently predicts higher mortality in patients with ACS. The current underutilization of effective therapies may contribute to the poor outcome. There remains an important opportunity to improve care in this high-risk population.

In the prospective, multicenter Canadian Acute Coronary Syndromes Registry, in-hospital revascularization was independently associated with better 1-year survival only among patients with high-risk non-ST-elevation acute coronary syndromes stratified by the Global Registry of Acute Coronary Events risk score; similar benefits were not observed in the low- and intermediate-risk groups. The Global Registry of Acute Coronary Events risk score appears to be a useful risk stratification tool that identifies high-risk patients for whom more aggressive treatment is warranted.

Aims Previous studies have reported differences in the use of cardiovascular medications for acute coronary syndromes (ACSs) according to the sex of the patient. We analysed which clinical factors are associated with underutilization of evidence-based therapies in women. Methods and results From the Canadian Registry of ACS I and II, 6558 patients (4471 men and 2087 women) with a final diagnosis of ACS were selected for the current analysis. Covariates were chosen using the approach described by Blackstone. The final selected model included 23 patient clinical variables. Women were less likely than men to receive beta-blockers (75.76 vs. 79.24%; P < 0.01), lipid-modifying agents (56.37 vs. 65.44%; P < 0.0001), and angiotensin-converting enzyme (ACE)-inhibitors (55.52 vs. 59.99%; P < 0.01). Female sex and clinical decision not to investigate with cardiac catheterization were the strongest independent predictors for not receiving lipid-modifying agents and ACE-inhibitors. Age, Killip class 2, and Killip class 3/4 were significant independent predictors of underutilization of beta-blocker use. Women were older (69 ± 12 vs. 64 ± 12; P < 0.01) with a higher prevalence of Killip class ≥ 2 (19.95 vs. 15.54%; P < 0.068), and they were less likely to be referred for cardiac catheterization (41.9 vs. 49.6 %; P < 0.001). Conclusions The current findings demonstrate that underutilization of evidence-based therapies in women with ACS compared with men is associated with multiple factors related to the patient (age), the consequences of the disease (congestive heart failure), and the physician's assessment of patient risk (decision to catheterize). Female gender remains associated with underutilization of lipid-modifying agents and ACE-inhibitors despite adjustment for these confounders.

The aim of this study was to assess the efficacy and safety of an early invasive strategy post-fibrinolysis in relation to time from symptom onset to fibrinolysis in patients with ST-elevation myocardial infarction (STEMI). The Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) randomized 1,059 patients receiving fibrinolysis for STEMI to an early invasive strategy versus standard therapy. The primary end point was the composite of death, reinfarction, recurrent ischemia, new or worsening heart failure, or cardiogenic shock at 30 days. In this post hoc subgroup analysis, we examined the effect of an early invasive strategy on efficacy and safety outcomes after stratification by time from symptom onset to fibrinolysis (2 or ≥2 hours). Of 1,059 patients in TRANSFER-AMI, 557 (53%) received fibrinolysis2 hours and 502 (47%) ≥2 hours after symptom onset. Compared to patients who received fibrinolysis within 2 hours of symptoms, patients who received fibrinolysis ≥2 hours after symptom onset had higher Global Registry of Acute Coronary Events risk scores (median 127 vs 122, p = 0.004). The effect of an early invasive strategy did not differ between symptom-to-fibrinolysis time strata for the primary efficacy end point (p-heterogeneity = 0.67), 30-day mortality, the composite of death or reinfarction at 30 days, 6 months, or 1 year, or bleeding (all p-heterogeneity0.40). In conclusion, the efficacy and safety of an early invasive strategy in patients undergoing fibrinolysis for STEMI do not vary in relation to time (2 or ≥2 hours) from symptom onset to fibrinolysis.

The prognostic significance of prior heart failure in acute coronary syndromes has not been well studied. Accordingly, we evaluated the baseline characteristics, management patterns and clinical outcomes in patients with acute coronary syndromes who had prior heart failure.The study population consisted of acute coronary syndrome patients in the Global Registry of Acute Coronary Events, expanded Global Registry of Acute Coronary Events and Canadian Registry of Acute Coronary Events between 1999 and 2008. Of the 13,937 eligible patients (mean age 66±13 years, 33% female and 28.3% with ST-elevation myocardial infarction), 1498 (10.7%) patients had a history of heart failure. Those with prior heart failure tended to be older, female and had lower systolic blood pressure, higher Killip class and creatinine on presentation. Prior heart failure was also associated with significantly worse left ventricular systolic function and lower rates of cardiac catheterization and coronary revascularization. The group with previous heart failure had significantly higher rates of acute decompensated heart failure, cardiogenic shock, myocardial (re)infarction and mortality in hospital. In multivariable analysis, prior heart failure remained an independent predictor of in-hospital mortality (odds ratio 1.48, 95% confidence interval 1.08-2.03, p=0.015).Prior heart failure was associated with high risk features on presentation and adverse outcomes including higher adjusted in-hospital mortality in acute coronary syndrome patients. However, acute coronary syndrome patients with prior heart failure were less likely to receive evidence-based therapies, suggesting potential opportunities to target more intensive treatment to improve their outcome.

Compared with non-smokers, cigarette smokers with ST-segment elevation myocardial infarctions derive greater benefit from fibrinolytic therapy. However, it is not known whether the optimal treatment strategy after fibrinolysis differs on the basis of smoking status. The Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) randomized patients with ST-segment elevation myocardial infarctions to a routine early invasive (pharmacoinvasive) versus a standard (early transfer only for rescue percutaneous coronary intervention or delayed angiography) strategy after fibrinolysis. The efficacy of these strategies was compared in 1,051 patients on the basis of their smoking status. Treatment heterogeneity was assessed between smokers and non-smokers, and multivariable analysis was performed to evaluate for an interaction between smoking status and treatment strategy after adjusting for baseline Global Registry of Acute Coronary Events (GRACE) risk score. Smokers (n = 448) were younger, had fewer cardiovascular risk factors, and had lower GRACE risk scores. They had a lower rate of the primary composite end point of 30-day mortality, reinfarction, recurrent ischemia, heart failure, or cardiogenic shock and fewer deaths or reinfarctions at 6 months and 1 year. Smoking status was not a significant predictor of either primary or secondary end points in multivariable analysis. Pharmacoinvasive management reduced the primary end point compared with standard therapy in smokers (7.7% vs 13.6%, p = 0.04) and non-smokers (13.1% vs 19.7%, p = 0.03). Smoking status did not modify treatment effect on any measured outcomes (p >0.10 for all). In conclusion, compared with non-smokers, current smokers receiving either standard or early invasive management of ST-segment elevation myocardial infarction after fibrinolysis have more favorable outcomes, which is likely attributable to their better baseline risk profile. The beneficial treatment effect of a pharmacoinvasive strategy is consistent in smokers and non-smokers.

Although the adverse prognosis of Q-waves on electrocardiogram (ECG) has been demonstrated, the prognostic significance of prominent R wave (PRW) in V1 or V2 across a broad spectrum of acute coronary syndrome (ACS) has not been specifically studied. In the Global Registry of Acute Coronary Events (GRACE) and the Canadian ACS Registry I ECG substudies, admission ECGs were analyzed in an independent core ECG laboratory. PRW was defined as R wave >40 to 50 ms in V1 or V2, R/S ≥1 in V1, or R/S ≥1.5 in V2. Among 11,895 patients with ACS, 495 (4.2%) had PRW; they were less likely to have a history of hypertension or heart failure and had lower GRACE risk scores, but a higher incidence of ST-segment depression (all p ≤0.001). Patients with PRW had similar rates of in-hospital death (2.8% vs 4.1%, respectively, p = 0.15) but lower rates of in-hospital heart failure (8.5% vs 15.2%, respectively, p = 0.02) and 6-month mortality (4.6% vs 8.4%, respectively, p = 0.004). In multivariable analyses, PRW was not a significant independent predictor of in-hospital mortality (adjusted odds ratio = 0.99, 95% confidence interval 0.55 to 1.8) or 6-month mortality (adjusted odds ratio = 0.70, 95% confidence interval 0.43 to 1.15). Among 4,418 patients who underwent coronary angiography, those with PRW had a higher prevalence of left circumflex artery disease (62.5% vs 49.5%, respectively, p = 0.01). In conclusion, across the broad spectrum of patients with ACS, PRW provides no significant additional prognostic utility beyond comprehensive risk assessment using the GRACE risk score. PRW is more frequently associated with left circumflex artery disease.

Background The aim of this study is to determine the test-retest reliability of the measurement of regional myocardial function by cardiovascular magnetic resonance (CMR) tagging using spatial modulation of magnetization. Methods Twenty-five participants underwent CMR tagging twice over 12 ± 7 days. To assess the role of slice orientation on strain measurement, two healthy volunteers had a first exam, followed by image acquisition repeated with slices rotated ±15 degrees out of true short axis, followed by a second exam in the true short axis plane. To assess the role of slice location, two healthy volunteers had whole heart tagging. The harmonic phase (HARP) method was used to analyze the tagged images. Peak midwall circumferential strain (Ecc), radial strain (Err), Lambda 1, Lambda 2, and Angle α were determined in basal, mid and apical slices. LV torsion, systolic and early diastolic circumferential strain and torsion rates were also determined. Results LV Ecc and torsion had excellent intra-, interobserver, and inter-study intra-class correlation coefficients (ICC range, 0.7 to 0.9). Err, Lambda 1, Lambda 2 and angle had excellent intra- and interobserver ICC than inter-study ICC. Angle had least inter-study reproducibility. Torsion rates had superior intra-, interobserver, and inter-study reproducibility to strain rates. The measurements of LV Ecc were comparable in all three slices with different short axis orientations (standard deviation of mean Ecc was 0.09, 0.18 and 0.16 at basal, mid and apical slices, respectively). The mean difference in LV Ecc between slices was more pronounced in most of the basal slices compared to the rest of the heart. Conclusions Intraobserver and interobserver reproducibility of all strain and torsion parameters was excellent. Inter-study reproducibility of CMR tagging by SPAMM varied between different parameters as described in the results above and was superior for Ecc and LV torsion. The variation in LV Ecc measurement due to altered slice orientation is negligible compared to the variation due to slice location. Trial registration This trial is registered as NCT00005487 at National Heart, Lung and Blood institute.

Background ST-segment depression (STD) is predictive of adverse outcomes in non–ST-segment elevation acute coronary syndromes (NSTE-ACS), but there are conflicting data on the incremental prognostic value of T-wave inversions (TWIs) on the admission electrocardiogram. Methods Admission electrocardiograms of 7,343 patients with NSTE-ACS from the Global Registry of Acute Coronary Events (GRACE) and ACS I registry were independently analyzed at a core laboratory and stratified by TWI and STD status. We performed multivariable analyses to determine the independent prognostic significance of TWI and tested for interaction between TWI and STD for adverse outcomes. Results Patients with TWI and/or STD had a higher prevalence of cardiovascular risk factors, higher Killip class, and higher GRACE risk scores. Among the 2,708 patients with available angiographic data, rates of 3-vessel or left main disease were similar between patients with TWI and those without TWI/STD. After adjusting for other established prognosticators, TWI did not independently predict in-hospital (adjusted odds ratio 1.03, 95% CI 0.75-1.42, P = .85) or 6-month mortality (adjusted odds ratio 1.02, 95% CI 0.80-1.30, P = .88); STD remained a strong independent predictor. There was no interaction between TWI and STD for these outcomes. No contiguous lead groups or cumulative number of leads with TWI provided independent prognostic information. Conclusions TWI is associated with other high-risk clinical features but is not an independent predictor of adverse short- and long-term mortality in NSTE-ACS. T-wave inversion does not provide additional prognostication beyond the GRACE risk model, and its concomitant presence does not alter the prognostic value of STD.