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Mycobacterium tuberculosis, the pathogen that causes tuberculosis, exhibits complex host–pathogen interactions. Pattern recognition receptors and their downstream signaling pathways play crucial roles in determining the outcome of infection. In particular, the scaffold protein β-arrestin 2 mediates downstream signaling of G protein–coupled receptors. However, the role of β-arrestin 2 in conferring immunity against M. tuberculosis has not yet been explored. We found that β-arrestin 2 was upregulated in the lesioned regions of lung tissues in patients with tuberculosis. M. tuberculosis infection upregulated β-arrestin 2 expression in human macrophages, and silencing of β-arrestin 2 significantly enhanced bactericidal activity by enhancing the expression of proinflammatory cytokines such as TNF-α. β-Arrestin 2 was shown to inhibit the activation of the TLR2/ERK1/2 pathway and its transcriptional regulation activity upon M. tuberculosis infection. Furthermore, β-arrestin 2 transcriptionally regulates TNF-α by binding to CREB1. These observations revealed that the upregulation of β-arrestin 2 is critical for M. tuberculosis to escape immune surveillance through an unknown mechanism. Our research offers a novel interference modality to enhance the immune response against tuberculosis by targeting β-arrestin 2 to modulate the TLR2–β-arrestin 2–ERK1/2–CREB1–TNF-α regulatory axis.

Deubiquitinases (DUBs) regulate diverse biological processes and represent a novel class of drug targets. However, the biological function of only a small fraction of DUBs, especially in adaptive immune response regulation, is well-defined. In this study, we identified DUB ubiquitin-specific peptidase 12 (USP12) as a critical regulator of CD4+ T cell activation. USP12 plays an intrinsic role in promoting the CD4+ T cell phenotype, including differentiation, activation, and proliferation. Although USP12-deficient CD4+ T cells protected mice from autoimmune diseases, the immune response against bacterial infection was subdued. USP12 stabilized B cell lymphoma/leukemia 10 (BCL10) by deubiquitinating, and thereby activated the NF-κB signaling pathway. Interestingly, this USP12 regulatory mechanism was identified in CD4+ T cells, but not in CD8+ T cells. Our study results showed that USP12 activated CD4+ T cell signaling, and targeting USP12 might help develop therapeutic interventions for treating inflammatory diseases or pathogen infections.

Vitamin B6 is necessary to maintain normal metabolism and immune response, especially the anti‐inflammatory immune response. However, the exact mechanism by which vitamin B6 plays the anti‐inflammatory role is still unclear. Here, we report a novel mechanism of preventing excessive inflammation by vitamin B6 via reduction in the accumulation of sphingosine‐1‐phosphate (S1P) in a S1P lyase (SPL)‐dependent manner in macrophages. Vitamin B6 supplementation decreased the expression of pro‐inflammatory cytokines by suppressing nuclear factor‐κB and mitogen‐activated protein kinases signalling pathways. Furthermore, vitamin B6–reduced accumulation of S1P by promoting SPL activity. The anti‐inflammatory effects of vitamin B6 were inhibited by S1P supplementation or SPL deficiency. Importantly, vitamin B6 supplementation protected mice from lethal endotoxic shock and attenuated experimental autoimmune encephalomyelitis progression. Collectively, these findings revealed a novel anti‐inflammatory mechanism of vitamin B6 and provided guidance on its clinical use.

NOD-like receptor (NLR) family CARD domain containing 3 (NLRC3), an intracellular member of NLR family, is a negative regulator of inflammatory signaling pathways in innate and adaptive immune cells. Previous reports have shown that NLRC3 is expressed in dendritic cells (DCs). However, the role of NLRC3 in DC activation and immunogenicity is unclear. In the present study, we find that NLRC3 attenuates the antigen-presenting function of DCs and their ability to activate and polarize CD4+ T cells into Th1 and Th17 subsets. Loss of NLRC3 promotes pathogenic Th1 and Th17 responses and enhanced experimental autoimmune encephalomyelitis (EAE) development. NLRC3 negatively regulates the antigen-presenting function of DCs via p38 signaling pathway. Vaccination with NLRC3-overexpressed DCs reduces EAE progression. Our findings support that NLRC3 serves as a potential target for treating adaptive immune responses driving multiple sclerosis and other autoimmune disorders.

Mycobacterium tuberculosis, which primarily infects mononuclear phagocytes, remains the leading bacterial cause of enormous morbidity and mortality because of bacterial infections in humans throughout the world. The IL-1 family of cytokines is critical for host resistance to M. tuberculosis. As a newly discovered subgroup of the IL-1 family, although IL-36 cytokines have been proven to play roles in protection against M. tuberculosis infection, the antibacterial mechanisms are poorly understood. In this study, we demonstrated that IL-36γ conferred to human monocyte-derived macrophages bacterial resistance through activation of autophagy as well as induction of WNT5A, a reported downstream effector of IL-1 involved in several inflammatory diseases. Further studies showed that WNT5A could enhance autophagy of monocyte-derived macrophages by inducing cyclooxygenase-2 (COX-2) expression and in turn decrease phosphorylation of AKT/mTOR via noncanonical WNT signaling. Consistently, the underlying molecular mechanisms of IL-36γ function are also mediated by the COX-2/AKT/mTOR signaling axis. Altogether, our findings reveal a novel activity for IL-36γ as an inducer of autophagy, which represents a critical inflammatory cytokine that control the outcome of M. tuberculosis infection in human macrophages.

The aim of the present study was to investigate the treatment effects and associated mechanism of Bak Foong pills (BFPs) combined with metformin in the treatment of polycystic ovarian syndrome (PCOS). BFPs and/or metformin were administrated to treat the PCOS rats, and the weights and morphologies of the ovary, uterus and adrenal gland were measured. The levels of fasting blood glucose (FBG), serum testosterone (T), luteinizing hormone, fasting insulin (FIN) and insulin-like growth factor-1 were also measured, and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The expression level of androgen receptor (AR) in the ovarian tissue, and the cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) mRNA levels in the ovary and adrenal tissues were detected. The levels of T, FIN, FBG and HOMA-IR in the combination group were significantly reduced; the wet weights of the ovary and the adrenal gland were decreased significantly, while that of the uterus was increased, and the histological morphology benignly recovered. The rats of each treatment group all experienced restored ovulation. The AR expression level in the treatment group was reduced, and the P450scc mRNA levels in the ovary and the adrenal gland of the combined treatment group were decreased. BFPs combined with metformin significantly affected PCOS, and the possible mechanism involved in the treatment may have been through the reduction of P450scc generation. BFPs may reduce the androgen levels, thus allowing the ovary to restore ovulation.

Objectives We evaluated inter-reader agreement of the ST-segment between two electrocardiogram (ECG) core laboratories. Background Accurate measurement of the ST-segment is key to diagnosis and management of acute coronary syndromes (ACS). Clinical trials also rely on adherence to the pre-specified ECG eligibility criteria. Methods 150 patients (100 ST-segment elevation (STE)-ACS, 50 non-STE-ACS) were selected. An experienced ECG reader from each laboratory measured ST-segment deviation on the baseline ECGs (nearest 0.1 mm). Results ∑ ST-segment deviation showed excellent inter-reader agreement (R = 0.965, intraclass correlation coefficient (ICC) 0.949, 95% CI (0.930–0.963)). Similar agreement was observed when ∑ ST-segment elevation (∑ STE) and ∑ ST-segment depression (∑ STD) were assessed separately. Better agreement was evident in STE-ACS cohort (ICC (95% CI): 0.968 (0.953–0.978, 0.969 (0.954–0.979), 0.931 (0.899–0.953)) compared to NSTE-ACS patients (ICC (95% CI): 0.860 (0.768–0.917), 0.816 (0.699–0.890), 0.753 (0.605–0.851) across measurement of ∑ ST-segment deviation, ∑ STE, and ∑ STD. Conclusions We demonstrated excellent agreement on ST-segment measurements between two experienced readers from two ECG core laboratories.

Lead aVR ST-segment deviation has been associated with increased mortality in ST-elevation myocardial infarction patients treated with fibrinolysis. However, its prognostic value in a contemporaneous population undergoing primary percutaneous coronary intervention is unknown.A core laboratory examined the 12-lead baseline electrocardiogram in 5,683 patients presenting within 6 hours of symptom onset in the APEX-AMI trial, and readers were blinded to study treatment and clinical outcomes. aVR ST-deviation was significantly associated with 90-day death when compared with patients with no aVR ST-deviation (aVR ST-depression [ST-D] 5%, aVR ST-elevation [ST-E] 10.2%, no ST-deviation [N] aVR 3.8%, P.001). After multivariable adjustment, aVR ST-E was strongly associated with 90-day death in inferior myocardial infarction (MI) (adjusted hazard ratio [HR] 5.87, 95% CI 2.09-16.5), whereas aVR ST-D was associated with excess mortality in noninferior MI (1.53, 1.06-2.22; P [interaction].001). aVR ST-E was also significantly associated with the presence of left main coronary (N aVR 1.8%, aVR ST-E 7.7%, P ≤ .001) and multivessel coronary disease (N aVR 41.3%, aVR ST-E 53.3%, P ≤ .001).Lead aVR ST-deviation is common, occurring in one-third of all ST-elevation myocardial infarction patients and independently associated with increased 90-day death. Myocardial infarction location modulates the prognostic significance of aVR ST-deviation such that lead aVR ST-E in inferior MI and ST-D in noninferior MI represent 2 high-risk groups. There was also more frequent advanced coronary disease in patients with aVR ST-E.

Aborted myocardial infarction (AbMI) in patients with ST-elevation MI defined by ST resolution with less than 2-fold elevation in biomarkers has been previously reported. We examined the association among AbMI, other metrics of infarct size, and left ventricular (LV) function defined by cardiac magnetic resonance (CMR).A total of 5745 patients with ST-elevation MI enrolled in the APEX-AMI trial, and 73 who were part of the CMR substudy within 3 to 5 days of randomization were evaluated. Core laboratories analyzed electrocardiograms, angiograms, and CMR images.Aborted MI (peak creatine kinase/creatine kinase MB2× upper limit of normal) with typical evolutionary electrocardiogram changes was observed in 11% (437/3938) overall and in 19% (14/73) of patients within the CMR study. Patients with AbMI were older (62 vs 60 years, P = .003) and tended to achieve complete STE-resolution post-percutaneous coronary intervention (≥70% resolution: 64% vs 32%; P = .076) compared with patients with MI. Cardiac magnetic resonance revealed that patients with AbMI had a smaller infarct size (4.7% vs 14.9% LV, P.001), less "no reflow" (0.9% vs 1.7% LV, P = .017), enhanced LV function (ejection fraction 54.4% vs 46.5%, P = .064), smaller LV end-systolic volumes (46.5 mL vs 67.2 mL, P = .009), and less transmurality (21.4% vs 50.9% with at least 1 segment with75% wall thickness, P = .046) when compared with patients with MI.Patients with AbMI had smaller subendocardial infarcts with enhanced LV size and function. Cardiac magnetic resonance provides corroborative evidence of AbMI and insights into its pathophysiology, specifically rapid successful reperfusion leading to limitation of the "wavefront" of infarct to the subendocardium.

Background The reduced expression of the Adenomatous polyposis coli (APC) gene, a tumor suppressor gene, through promoter hypermethylation has been reported to play a key role in the carcinogenesis. However, the correlation between APC promoter hypermethylation and ovarian cancer (OC) remains to be clarified. Methods A comprehensive literature search was carried out in related research databases. The overall odds ratio (OR) and corresponding 95 % confidence interval (CI) were used to evaluate the effects of APC promoter hypermethylation on OC and clinicopathological characteristics. Results Ultimately, 12 eligible studies were used in our study, including 806 OC samples, 429 normal controls, 109 benign lesions and 75 LMP samples. The pooled OR showed that APC promoter hypermethylation was significantly higher in OC than in normal and benign controls (OR = 6.18 and OR = 3.26, respectively). No significant correlation was observed between OC and low malignant potential (LMP) tumors (P = 0.436). In the comparison of OC and normal controls, subgroup analysis based on race showed that the overall OR of APC promoter hypermethylation was significant and similar in Asians and Caucasians (OR = 8.34 and OR = 5.39, respectively). A subgroup analysis based on sample type found that the pooled OR was significantly higher in blood than in tissue (OR = 18.71 and OR = 5.74, respectively). A significant association was not observed between APC promoter hypermethylation and tumor grade or tumor stage. The pooled OR indicated that APC promoter hypermethylation was significantly lower in serous carcinoma than in non-serous carcinoma (OR = 0.56, P = 0.02). No obvious publication bias was detected by Egger’s test (all P > 0.05). Conclusions APC promoter hypermethylation may be linked to the increased risk of OC. It was associated with histological type, but not with tumor grade or tumor stage. Moreover, hypermethylated APC may be a noninvasive biomarker using blood samples. Future studies are required to validate these results.

Early restoration of blood flow of the infarct-related artery is associated with an improved outcome in patients with ST-elevation myocardial infarction (STEMI). Previous studies have shown a low mortality in patients with TIMI 3 flow before primary percutaneous coronary intervention (PCI). Most likely these patients had spontaneous recanalization of the infarct vessel and might constitute a low-risk subgroup. The purpose of the present analysis was to investigate whether TIMI 3 flow obtained with fibrinolysis before PCI is associated with a clinical outcome comparable to that in patients with spontaneous TIMI 3 flow.Patients with STEMI6 hours enrolled in the ASSENT-4 PCI study were randomized to facilitated PCI with tenecteplase or primary PCI. For this analysis, patients were divided into three groups according to the TIMI flow of the infarct vessel before PCI: TIMI 0/1, TIMI 2, and TIMI 3.From a total of 1617 patients, 861 had TIMI 0/1, 279 had TIMI 2, and 477 TIMI 3 flow. The rates of TIMI 3 flow after PCI were 84.6, 89.7, and 95.6%, respectively. Complete ST resolution was observed most often in the TIMI 3 flow group (47.5, 53.6, and 58.6%). The incidence of cardiogenic shock (6.2, 5.5, and 3.6%) and 90-day mortality (6.1, 4.7, and 4.0%) were lowest in the group with TIMI 3 patency before PCI, respectively. The rate of TIMI 3 flow before PCI was higher in the facilitated PCI group than in the primary PCI group (43.9 vs. 15.2%). The 90-day mortality in patients with TIMI 3 before PCI was identical in the facilitated and the primary PCI groups (14/353, 4.0% vs. 5/124, 4.0%).In this post-hoc analysis of ASSENT-4 PCI, TIMI grade 3 flow in the infarct-related artery before PCI, occurring either spontaneously or obtained by fibrinolysis, is associated with a higher TIMI patency after PCI, better improved ST resolution and a trend towards a favourable clinical outcome after 90 days.

Background: Baseline Q waves may provide additional value compared with time from the onset of symptoms in predicting outcomes for patients with ST-segment elevation. We evaluated whether baseline Q waves superseded time from symptom onset as a prognostic marker of one-year mortality in patients with ST-segment elevation acute coronary syndrome. Our study was derived from data from patients undergoing primary percutaneous coronary intervention within 24 hours in the PLATelet inhibition and patient Outcomes trial Methods: Q waves on the baseline electrocardiogram were evaluated by a blinded core laboratory. We assessed the associations between baseline Q waves and time from symptom onset to percutaneous coronary intervention with peak biomarkers, ST-segment resolution on the discharge electrocardiogram, and one-year all-cause and vascular mortality. Results: Of 4341 patients with ST-segment elevation, 46% had baseline Q waves. Compared to those without Q waves, those with baseline Q waves were older, more frequently male, had higher heart rates, more advanced Killip class and had a longer time between the onset of symptoms and percutaneous coronary intervention. They also had higher one-year all-cause mortality than patients without baseline Q waves (baseline Q waves: 4.9%; no baseline Q waves: 2.8%; hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.29–2.45, p p = 0.046) and vascular mortality (adjusted HR 1.58, 95% CI 1.09–2.28, p = 0.02). Interpretation: The presence of baseline Q waves provides useful additional prognostic insight into the clinical outcome of patients with ST-segment elevation. Clinical Trials.gov registration no. NCT00391872

Background— Ticagrelor, when compared with clopidogrel, reduced the 12-month risk of vascular death/myocardial infarction and stroke in patients with ST-elevation acute coronary syndromes intended to undergo primary percutaneous coronary intervention in the PLATelet inhibition and patient Outcomes (PLATO) trial. This prespecified ECG substudy explored whether ticagrelor's association with vascular death and myocardial infarction within 1 year would be amplified by (1) the extent of baseline ST shift and (2) subsequently associated with fewer residual ST changes at hospital discharge. Methods and Results— ECGs were evaluated centrally in a core laboratory in 3122 ticagrelor- and 3084 clopidogrel-assigned patients having at least 1 mm ST-elevation in 2 contiguous leads as identified by site investigators on the qualifying ECG. Patients with greater ST-segment shift at baseline had higher rates of vascular death/myocardial infarction within 1 year. Among those who also had an ECG at hospital discharge (n=4798), patients with ≥50% ΣST-deviation (ΣST-dev) resolution had higher event-free survival than those with incomplete resolution (6.4% versus 8.8%, adjusted hazard ratio 0.69 (0.54–0.88), P =0.003). The extent of ΣST-dev resolution was similar irrespective of treatment assignment. The benefit of ticagrelor versus clopidogrel on clinical events was consistent irrespective of the extent of baseline ΣST-dev ( P (interaction)=0.728). When stratified according to conventional times from symptom onset, ie, ≤3 hours, 3 to 6 hours, >6 hours, the extent of baseline ΣST-dev declined progressively over time. As time from symptom onset increased beyond 3 hours, the benefit of ticagrelor appeared to be more pronounced; however, the interaction between time and treatment was not significant ( P =0.175). Conclusions— Ticagrelor did not modify ΣST-dev resolution at discharge nor was its benefit affected by the extent of baseline ΣST-dev. These hypothesis-generating observations suggest that the main effects of ticagrelor may not relate to the rapidity or the completeness of acute reperfusion, but rather the prevention of recurrent vascular events by more powerful platelet inhibition or other mechanisms. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00391872.

We compared the clinical features, laboratory and coronary angiographic findings, treatments, and outcomes among patients with ST-segment elevation myocardial infarction (MI) with and without left bundle branch block (LBBB). We examined 5,742 patients with ST-segment elevation MI with and without LBBB treated with primary percutaneous coronary intervention in the Assessment of Pexelizumab in Acute Myocardial Infarction trial. The main outcome measures were obstructive coronary disease, MI, positive cardiac biomarkers, angiographic Thrombolysis In Myocardial Infarction flow, and death, MI, or congestive heart failure at 90 days. LBBB was present in 98 patients (1.7%). According to the protocol, patients with LBBB were eligible only if they had ≥1 mm concordant ST-segment elevation. Obstructive coronary artery disease was present in >87% of the patients with LBBB. Documented MI (elevated biomarkers) with an initially occluded infarct artery was more common in patients with LBBB with concordant ST-segment elevation (71.4%) than in patients without (44.1%; p = 0.027). The use of ST-segment elevation concordance criteria in the presence of LBBB was more often associated with documented MI with an identifiable culprit vessel with an initially occluded infarct-related artery. In conclusion, because a substantial proportion of patients with LBBB have acute MI with a culprit lesion and positive biomarkers, these data support immediate catheterization with the intent for primary percutaneous coronary intervention for all patients presenting with suspected ST-segment elevation myocardial infarction, ischemic symptoms, and presumed new LBBB, particularly if concordant ST-segment elevation is present.

Contemporary non-ST-elevation myocardial infarction-acute coronary syndrome guidelines emphasize early-risk stratification and optimizing therapy including an invasive strategy in high-risk patients. To assess the feasibility of initiating this strategy in the prehospital environment, we examined how such patients are transported to hospital, their risk profile, and the proportion potentially eligible for such a strategy.Consecutive patients with ST-segment elevation myocardial infarction admitted in Edmonton were studied between September and November 2008 and divided according to their mode of transport to hospital: emergency medical services (EMS) versus self-presenting. Baseline characteristics, GRACE Risk Score, blinded core laboratory electrocardiogram analysis, cardiac biomarkers, in-hospital procedures, and outcomes were analyzed.Thirty-five percent (93/263) of patients presented via EMS and often to percutaneous coronary intervention hospitals, that is, 64.5% versus 44.1% (P = .0016). They were older (75 vs 62 years, P.001), more often female (43% vs 28.1%, P.001), diabetic (34.4% vs 22.9%, P = .045), and hypertensive (72.0% vs 57.1%, P = .017) and had higher GRACE Risk Scores (median 166 vs 130, P.001). Electrocardiogram analysis revealed more baseline Q waves (38.8% vs 25.5%, P = .031) and ST depression ≥2 mm (P = .027) in EMS-transported patients. Fewer EMS patients underwent cardiac catheterization (60.2% vs 88.2%, P.001), and a paradoxical relationship existed between catheterization rates and GRACE Risk Score in the total cohort (low-risk: 93.4% vs high-risk: 59.3%, P.001). The composite of death/re-myocardial infarction/congestive heart failure/shock was greater in EMS patients (unadjusted odds ratio 3.96, 95% CI 1.80-8.69, P = .001); these differences were attenuated after GRACE Risk Score adjustment.Regional strategies using risk-based triage, early medical therapy, and timely triage to percutaneous coronary intervention centers represents an unrealized opportunity to enhance ST-segment elevation myocardial infarction care.

Background ST-elevation myocardial infarction (STEMI) patients with a prior MI history have worse outcomes. The prognostic significance of silent MI (pathologic Q waves outside the ST-elevation territory) in STEMI is unclear. Methods A total of 5,733 STEMI patients from 296 clinical centers in 17 countries were classified as (1) silent MI—baseline Q waves outside the infarct-related artery territory and no history of prior MI, (2) history of prior MI (HxMI), or (3) no prior MI. Results Of 5,733 STEMI patients, 419 (7.3%) had silent MI, 693 (12.1%) had HxMI, and 4,621 (80.6%) had no prior MI. Ninety-day death and death/congestive heart failure/shock were higher in patients with HxMI (8.4% and 15.3%, respectively) and silent MI (6.7% and 13.9%, respectively) compared with patients with no prior MI (4.0% and 9.1%, respectively) ( P ≤ .001 for all). After baseline adjustment, patients with HxMI were at increased risk for 90-day death (adjusted hazard ratio [HR] 1.62, 95% CI 1.18-2.21), whereas both those with HxMI and those with silent MI had increased risk of 90-day death/congestive heart failure/shock compared with those with no prior MI (adjusted HR 1.54, 95% CI 1.23-1.93 and adjusted HR 1.46, 95% CI 1.10-1.93, respectively). Conclusions Seven percent of STEMI patients had a silent MI. They represent a novel subgroup at increased risk comparable to those with known prior MI. Hence, in future studies, acquiring baseline Q wave data outside the distribution of acute injury should broaden the prognostic insights from STEMI patients with a prior MI.

To evaluate the prognostic impact of ST depression resolution among patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial.In this study, 4729 of 5745 patients had analysable ECGs demonstrating concomitant ST-segment depression. Resolution of summation operatorST elevation (STE-R) and summation operatorST depression (STD-R) on 30 min post-PCI ECGs was dichotomized into those withor =50 vs.50% ST-segment resolution. Overall, 1143 patients (24%) had STD-R50%. These patients had higher risk characteristics including older age, female sex, diabetes, hypertension, prior CHF/MI, Killip classI, triple vessel disease, and less frequent TIMI 3 flow in the culprit coronary vessel post-PCI. After multivariable adjustment and accounting for STE-R, STD-R50% remained an independent predictor for 90 day death and the composite of death, cardiogenic shock, or CHF. When compared with patients with both STE-R and STD-Ror =50%, patients with both STE-R and STD-R50% had the worst outcomes [hazard ratios (HR) 90 day death: 2.54; 95% confidence intervals (CI): 1.71-3.77; HR 90 day composite: 2.18; 95% CI: 1.63-2.91].When ST depression is present in STEMI patients undergoing primary PCI, STD-R50% provides independent prognostic value that is incremental to STE-R.

Reperfusion with primary percutaneous intervention (PCI) in ST-segment elevation myocardial infarction leads to improved clinical outcomes. The contribution angiographic vs electrocardiographic reperfusion parameters confer on prognosis is unclear.A prespecified subset of the APEX-AMI trial patients was analyzed by independent angiographic and electrocardiographic core laboratories (n = 1,018). Angiographic reperfusion after PCI and electrocardiogram 30 minutes post-PCI were assessed.Of the 941 patients in the angiographic substudy, 796 (85%) attained post-PCI Thrombolysis In Myocardial Infarction (TIMI) flow 3 and 852 (91%) had TIMI Myocardial Perfusion Grade (TMPG) 2/3. There were 664 (71%) patients with residual ST elevation (ST-E)2 mm. Ninety-day mortality and death/CHF/shock were lower in patients with TIMI flow 3 vs3 (1.9% vs 6.2%, P = .002; 5.8% vs 10.4%, P = .044) and those with TMPG 2/3 vs 0/1 (2.0% vs 7.9%, P = .001; 6.0% vs 11.9%, P = .028). Patients with residual ST-E2 mm had similar rates of mortality as those withor =2 mm (2.3% vs 3.3%, P = .374) but lower rates of death/CHF/shock (5.2% vs 9.6%, P = .013). After multivariable adjustment, only post-PCI TMPG 2/3 was significantly associated with survival (P = .001), whereas residual ST-E (P = .606) and post-PCI TIMI flow grade (P = .086) were not. Conversely, residual ST-Eor =2 mm (P = .012) rather than angiographic reperfusion was associated with the composite of death/CHF/shock events.Angiographic and electrocardiographic estimates of reperfusion with primary PCI in ST-segment elevation myocardial infarction provide different and complementary predictions of morbidity and mortality.

Spontaneous reperfusion (SR) in ST elevation myocardial infarction (STEMI) improves clinical outcome, yet its incidence and impact among diabetic patients is unclear.To carry out a systematic analysis of SR in the diabetic cohort of a large primary percutaneous coronary intervention (PCI)-treated population with STEMI.4944 patients (15.5% diabetic) undergoing primary PCI in the APEX AMI study were evaluated. SR defined as pre-PCI Thrombolysis in Myocardial Infarction (TIMI) 3 flow occurred in 11.5% of patients; it was more common in non-diabetic (11.9%) than in diabetic patients (9.2%) (p = 0.028). Patients with SR versus no SR had improved post-PCI TIMI 3 flow: in non-diabetic patients (99.8% vs 90.3%, p0.001) and in diabetic patients (98.6% vs 84.9%, p0.001). Non-diabetic patients with SR showed a significant improvement in 90-day death/shock/congestive heart failure (CHF) compared with those without SR: 4.4% versus 8.9% (p = 0.001), respectively. The composite outcome in diabetic patients with versus without SR was 10.0% versus 14.9% (p = 0.270), respectively. When outcomes were examined according to tertiles of baseline blood glucose, both non-diabetic and diabetic patients with normoglycaemia showed higher SR rates (15.5%, 10.3%, 7.3% for non-diabetic patients, p0.001; 17.4%, 7.2%, 9.1% for diabetic patients, p = 0.132), greater ST resolution (55.4%, 52.6%, 49.7% for non-diabetic patients, p = 0.030; 50%, 46.4%, 39.1% for diabetic patients, p = 0.179), and improved 90-day death/shock/CHF (5.2%, 8.3%, 14% for non-diabetic patients p0.001; 8.7%, 4.2%, 15.8% for diabetic patients, p = 0.006).These data indicate that SR is less common in diabetic patients with STEMI. Diabetic patients without SR have worse post-PCI epicardial patency, which contributes to adverse outcomes. Diabetic patients with normal baseline blood glucose and SR have enhanced epicardial flow after PCI and improved prognosis.

Because acute occlusion of coronary arteries supplying the inferolateral myocardium frequently eludes standard 12-lead electrocardiogram (ECG) diagnosis, these patients may present as non-ST-segment elevation acute coronary syndromes (NSTE-ACS).We examined culprit artery occlusion among 1,957 NSTE-ACS patients in the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network trial who underwent diagnostic coronary angiography. We compared baseline characteristics, electrocardiographic findings, in-hospital treatment, and long-term outcomes between patients with and without occluded culprit arteries.The culprit artery was occluded in 528 (27%) patients. Culprit lesions were more frequently identified in the inferolateral territory among patients with an occluded culprit artery (63%) compared with those with a nonoccluded artery (45%, P.0001). Patients with an occluded culprit artery were younger, more often male, and more likely to have had a prior myocardial infarction. Despite similar in-hospital treatment, patients with an occluded culprit artery had larger infarcts (median peak creatine kinase-MB 4.3 vs 2.1 x upper limit of normal, P.0001) and higher risk-adjusted 6-month mortality (hazard ratio 1.72, 95% CI 1.07-2.79).More than 25% of NSTE-ACS patients had an occluded culprit artery on angiography. These patients may represent ST-segment elevation myocardial infarction equivalents; thus, improved early risk stratification techniques would help more rapidly triage these high-risk patients to an early invasive management strategy.

ObjectivesWe assessed the incremental value of baseline Q waves over time from symptom onset as a marker of clinical outcome in ST-segment elevation myocardial infarction (STEMI).BackgroundTime from symptom onset is a central focus in STEMI patients. The presence of Q waves on the baseline electrocardiogram (ECG) has been suggested to be of incremental value to time from symptom onset in evaluating clinical outcomes.MethodsWe evaluated baseline Q waves and ST-segment resolution 30 min after primary percutaneous intervention (PCI) ECGs in 4,530 STEMI patients without prior infarction. Additionally, peak biomarkers; 90-day mortality; and the composite of death, congestive heart failure (CHF), or cardiogenic shock were assessed.ResultsFifty-six percent of patients had baseline Q waves: they were older, more frequently male and diabetic, and had a more advanced Killip class. Patients with baseline Q waves had greater mortality and a higher composite rate of death, CHF, and shock versus patients without baseline Q waves at 90 days (5.3% vs. 2.1% and 12.1% vs. 4.8%, respectively, both p < 0.001). Complete ST-segment resolution was highest, whereas 90-day mortality and the composite outcome were lowest among those randomized ≤3 h without baseline Q waves. After multivariable adjustment, baseline Q-wave but not time from symptom onset was significantly associated with a 78% relative increase in the hazard of 90-day mortality and a 90% relative increase in the hazard of death, shock, and CHF.ConclusionsBaseline Q waves in STEMI patients treated with primary PCI provide an independent prognostic marker of clinical outcome. These data might be useful in designing future clinical trials as well as in evaluating patients for triage and potential transfer for planned primary PCI. (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction [APEX-AMI]; NCT00091637)

Guidelines recommend that patients with suggestive symptoms of myocardial ischemia and ST-segment elevation (STE) inor =2 adjacent electrocardiographic leads should receive immediate reperfusion therapy. Novel strategies aimed to reduce door-to-balloon time, such as prehospital wireless electrocardiographic transmission, may be dependent on the interpretation accuracy of the electrocardiogram (ECG) readers. We assessed the ability of experienced electrocardiographers to differentiate among STE, acute STE myocardial infarction (STEMI), and nonischemic STE (NISTE). A total of 116 consecutive ECGs showing STE were studied. Fifteen experienced cardiologists were asked to decide, based on the ECG and assuming that the patient had compatible symptoms, whether they would send each patient for primary percutaneous coronary intervention (PPCI). If NISTE was chosen, the reader selected 1 or more 12 possible options to explain the choice. Of 116 patients, only 8 had STEMI. The percentage of ECGs for which PPCI was recommended for the patient by the individual readers varied widely (7.8% to 33%). There was no significant difference between the North American and Other Countries readers (p = 0.13). The sensitivity and specificity of the individual readers ranged from 50% to 100% (average 75%) and 73% to 97% (average 85%), respectively. There were broad inconsistencies among the readers in the chosen reasons used to classify NISTE. In conclusion, we found wide variations among experienced electrocardiographers in reading ECGs with STE and differentiating STEMI with need for PPCI from NISTE. There is a need to revise our current electrocardiographic criteria for differentiating STEMI from NISTE.

AIM: To examine the association of left ventricular hypertrophy (LVH) on admission electrocardiography with adverse outcomes in acute coronary syndrome (ACS) patients. METHODS AND RESULTS: A total of 7443 non-ST-elevation ACS patients in Global Utilization of STrategies to Open occluded arteries (GUSTO) IV ACS trial had admission electrocardiograms analysed at a core laboratory. LVH [>or=20 mm Cornell voltage (LV voltage) (women) or >or=28 mm (men) plus strain patterns] was observed in 586 (7.9%) patients, and women accounted for 74%. LVH patients were also older and had more co-morbidities, ST-depression >or= 0.5 mm, elevated C-reactive protein and N-terminal pro-brain naturetic peptide (NT-proBNP), and lower troponin T. Invasive procedures occurred less often in LVH patients (cardiac catheterization: 31 vs. 38%, P = 0.001; percutaneous coronary intervention: 12 vs. 20%, P < 0.001). Mortality was significantly higher in patients with LVH (30 day: 5 vs. 3%, P = 0.046; 1 year: 14 vs. 7%, P < 0.001), whereas 30 day myocardial infarction (MI) and death/MI did not differ. After baseline adjustment including NT-proBNP, LVH remained associated with increased hazard of 1 year mortality in women, but not in men [P-interaction = 0.033; women: adjusted hazard ratio (LVH vs. no LVH): 1.42 (1.04-1.94), P = 0.029]. CONCLUSION: Electrocardiographic-LVH identifies an important subset of ACS patients with a higher risk of long-term mortality, particularly among women. These novel findings highlight opportunities to improve treatment and outcome among similar ACS patients. Udgivelsesdato: 2007-Sep

ST-segment depression (ST-D) on the admission electrocardiogram of patients with non-ST-elevation acute coronary syndromes (NSTEACSs) is associated with higher mortality. However, few studies have evaluated the effect of location of ST-D and T-wave polarity on long-term prognosis of patients with NSTEACS. Electrocardiographic (ECG) and clinical data from 6,770 patients with NSTEACS randomly assigned in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIB trial were analyzed retrospectively. One-year mortality was correlated with location of ST-D (leads I and aVL; II, III, and aVF; V1 to V3; or V4 to V6) and T-wave polarity. ST-D in any of the ECG locations was associated with higher mortality compared with patients without ST-D. Patients with ST-D and T-wave inversion in leads V4 to V6 had the highest 1-year mortality rate of all groups (16.2%), significantly higher compared with patients with ST-D without T-wave inversion in those leads (9.0%, p=0.001). Logistic regression analysis showed that age, hyperlipidemia, Killip class>I, history of myocardial infarction, history of heart failure, history of angina pectoris, systolic blood pressure, heart rate, sum of ST-D (odds ratio 1.061, 95% confidence interval 1.035 to 1.087, p

OBJECTIVES The purpose of this study was to develop 30-day and 1-year risk stratification models for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients that incorporate quantitative ST-segment depression and novel biomarkers. BACKGROUND Several novel biomarkers have changed the risk profile of ACS; thus, the reassessment of traditional indicators such as ST-segment depression in this new context is warranted. METHODS Multivariable logistic regression was used to identify significant predictors of 30-day death and death/myocardial infarction (MI) and 1-year mortality in 7,800 NSTE-ACS patients enrolled in the GUSTO-IV (Global Utilization of Strategies to Open Occluded Arteries-IV ACS) trial between 1998 and 2000. RESULTS Among all other predictors, the degree of ST-segment depression had the highest prognostic value for 30-day death, 30-day death/MI, and 1-year death. Troponin T (TnT), creatinine clearance, N-terminal pro-brain natriuretic peptide (NT-proBNP), heart rate, and age were also highly influential on adverse outcomes. Unlike TnT and NT-proBNP, C-reactive protein was only predictive of long-term death. In contrast to mortality, the contribution of TnT to predicting 30-day death/MI increased, whereas NT-proBNP's role was attenuated. The discriminatory power was excellent (c-index [adjusted for over-optimism]: 0.82 [30-day death]; 0.72 [30-day death/MI]; 0.81 [1-year]). CONCLUSIONS In this large contemporary study of NSTE-ACS patients, novel insights into risk stratification were observed-in particular, the utility of quantitative ST-segment depression and multiple biomarkers. Collection of these indicators in future NSTE-ACS populations is recommended to evaluate generalizability and clinical application of these findings.

Background Prior research suggests that patients may be entered into clinical trials with different electrocardiographic (ECG) findings than specified by study protocol criteria; the extent and impact of this variability in a large-scale trial have not been previously described. Methods We evaluated the relationship between case report form (CRF) categorization of the admission ECG and a Core Laboratory and subsequent outcome in a retrospective analysis of a trial of patients with acute ischemia and a broad spectrum of ECG changes (the GUSTO-IIb trial). Results In 11 037 patients with CRF information and an interpretable ECG, there was agreement in 89.1% of ST-elevation and 81.9% of non–ST-elevation cases. Among patients designated as having no ST elevation on the CRF, 1-year mortality rates were significantly higher in the subgroup of patients with Core Laboratory–determined ST elevation as compared with those where both the CRF and Core Laboratory classification were in agreement (8.8% vs 6.8%, P = .0093). Among patients designated as having ST elevation by the CRF, 1-year mortality rates were similar in both the subgroup of patients with and without Core Laboratory agreement (7.7% vs 8.2%, P = .72). Conclusions These findings have important implications for clinicians in routine practice because even a simple evaluation (presence or absence of ST elevation) on the admission ECG was often discordant and was associated with adverse clinical outcome.

Left bundle branch block (LBBB) complicates the diagnosis of acute myocardial infarction (AMI). The Sgarbossa criteria were developed from GUSTO I to surmount this diagnostic challenge but have not been prospectively validated in a large population with presumed AMI. We evaluated their utility in the diagnosis and risk stratification of AMI patients in ASSENT 23.Baseline electrocardiograms (ECG) of LBBB patients were scored using Sgarbossa's criteria (0-10) by 2 readers blinded to the CK/CK-MB data and clinical outcomes; 267 (1.2%) patients had LBBB on their baseline ECG.Among 253 LBBB patients with available peak CK/CK-MB data, 158 (62.5%) had peak CK/CK-MB levels2x ULN, thereby qualifying for the diagnosis of AMI. A Sgarbossa score of 3 was shown in 48.7% of LBBB patients with elevated CK/CK-MB versus in 12.6% of those without a CK/CK-MB rise (P.001). Patients with higher Sgarbossa scores, ie, 3, had a higher mortality compared with those with a score3, (23.5% vs 7.7% at 30 days P.001; and 33.7% vs 20.2% at 1 year, P.001, respectively).Our findings validate the utility of Sgarbossa criteria for diagnosing AMI in the setting of LBBB. These criteria provide a simple and practical diagnostic approach to risk stratify this diagnostically challenging high-risk group and optimize risk-benefit of acute therapy.

Background The relevance of the atrial coronary anatomy in the pathogenesis of atrial arrhythmias and atrioventricular (AV) block complicating acute myocardial infarction (AMI) remains unclear. Objectives We evaluated the location of the infarct-related coronary lesion relative to the principal atrial branches (ie, sinoatrial nodal, AV nodal, left atrial circumflex) in 454 patients with ST-elevation AMI in the CAPTORS II trial. Methods Patients underwent systematic 60-minute postfibrinolytic angiograms, and coronary anatomy was correlated with evidence of atrial arrhythmias and AV block on sequential electrocardiograms. Results Patients with either sinoatrial nodal or left atrial circumflex compromise (n = 34) had a higher incidence of “early” (ie, up to 90 minutes postfibrinolysis) atrial arrhythmias vs those without (23.5% vs 7.1%; P = .004). Patients with AV nodal compromise (n = 207) had a higher incidence of “early” AV block vs those without (12.1% vs 3.6%; P = .001). Conclusion These findings support the etiological role of acute atrial ischemia in the development of early atrial arrhythmias and AV block complicating AMI.

Serial forecasts of final myocardial infarct (MI) size during fibrinolytic treatment (Rx) of ST-elevation MI would allow the identification of high-risk patients with a predicted major loss of viable myocardium, at a point when treatment may still be modified. We investigated a model for such forecasting, using time and the ECG.We collected 234 patients with ST-elevation MI, without signs of previous MI, bundle branch block, or hypertrophy. MI size was determined by the Selvester score and was "forecasted" at: admission with patients stratified by delay time and an ECG acuteness score into three groups (EARLY, DISCORDANT, and LATE); 90 min after Rx byor =70% ST-recovery or not and occurrence of "reperfusion peaks"; 4 h after Rx by ST re-elevations. EARLY patients had smaller final infarct sizes than LATE (9.4 vs. 20%, P=0.01). EARLY patients withor =70% ST-recovery without a reperfusion peak had smaller infarct sizes than those with (3.1 vs. 12.5%, P=0.001). EARLY patients without ST re-elevations had smaller infarct sizes (1.5%) than those with some (9%) or many re-elevations (12%), P0.001.Final infarct size can be forecasted using delay time and serial ECGs. Serially updated forecasts seem especially important when both clock-time and initial ECG- signs indicate earliness.

Objectives The investigators undertook a systematic, comprehensive analysis of the therapeutic response and clinical outcomes of reperfusion therapy for acute ST-segment elevation myocardial infarction (STEMI) in 5,470 patients from the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 trial. Background Prompt effective reperfusion therapy for acute STEMI may attenuate major myocardial necrosis. Methods We prospectively collected sequential electrocardiographs and clinical data. Aborted myocardial infarction (MI) was defined as maximal creatine kinase ≤2× upper limit of normal coupled with typical evolutionary electrocardiographic changes. Results Of the patients, 727 (13.3%) had an aborted MI, with the highest frequency (25%) occurring in patients treated Conclusions Prompt fibrinolytic treatment improved the likelihood of aborted MI. The subgroup with complete 60-min ST-segment resolution had the best clinical outcomes.

Both ST resolution and Q-wave development postfibrinolysis provide important prognostic insights in patients with acute myocardial infarction (MI). However, the relative contributions of these 2 factors to risk assessment have not been examined prospectively.ST resolution and Q development were evaluated 24 to 36 hours (24-36 h) postfibrinolysis in ASSENT-2: 13,100 out of 16,949 patients who had both baseline and 24-36 h electrocardiograms free of confounders (left bundle branch block, ventricular rhythm, reinfarction before 24-36 h electrocardiograms) were included in this analysis. Q-wave MI evolved in 10,466 patients (79.9%) and 2634 patients (20.1%) had non-Q-wave MI at 24-36 h postfibrinolysis. Mortality rates at 1-year were 7.0% for patients with Q-wave MI and 5.8% for non-Q-wave MI patients, respectively (P =.046). Patients with Q-wave MI versus those without were less likely to have complete ST-segment resolution (49.1% vs 59.1%) and more likely to have partial (37.1% vs 27.8%) or no resolution (13.8% vs 13.1%) at 24 to 36 hours postfibrinolysis (P.001). Mortality rates at 1 year for Q-wave MI with complete, partial, and no resolution were 5.2%, 8.1%, and 10.1%, respectively (P.001), and for non-Q-wave MI with complete, partial, and no resolution were 4.5%, 7.6%, and 8.0% (P =.003).These results demonstrate the additional prognostic significance of ST-segment resolution to Q-wave development at 24 to 36 hours after fibrinolysis.

Aims ASSENT 3 (Assessment of the Safety and Efficacy of a New Thrombolytic) demonstrated that the bolus fibrinolytic tenecteplase (TNK), combined with enoxaparin (ENOX) or abciximab (ABCX), substantially reduced ischemic complications of acute myocardial infarction as compared with unfractionated heparin (UH). We compared ST resolution in each of the three treatment regimens in order to evaluate the speed, extent and stability of ST segment resolution and its relationship to the primary composite endpoint(s) of the trial. Methods and results We evaluated ST segment shift and its subsequent resolution i.e. complete (≥70%), partial (

Objectives Our primary objective was to examine the prognostic relationship between baseline quantitative ST-segment depression (ST↓) and cardiac troponin T (cTnT) elevation. The secondary objectives were to: 1) examine whether ST↓ provided additional insight into therapeutic efficacy of glycoprotein IIb/IIIa therapy similar to that demonstrated by cTnT; and 2) explore whether the time to evaluation impacted on each marker’s relative prognostic utility. Background The relationship between the baseline electrocardiogram (ECG) and cTnT measurements in risk-stratifying patients presenting with acute coronary syndromes (ACS) has not been evaluated comprehensively. Methods The study population consisted of 959 patients enrolled in the cTnT substudy of the Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON)-B trial. Patients were classified as having no ST↓ (n = 387), 1 mm ST↓ (n = 433), and ST↓ ≥2 mm (n = 139). Forty-percent (n = 381) were classified as cTnT-positive based on a definition of ≥0.1 ng/ml. Results Six-month death/(re)myocardial infarction rates were 8.4% among cTnT-negative patients with no ST↓ and 26.8% among cTnT-positive patients with ST↓ ≥2 mm. On ECGs done after 6 h of symptom onset, ST↓ ≥2 mm was associated with higher risk compared to its presence on ECGs done earlier (odds ratio [OR] 7.3 vs. 2.1). In contrast, the presence of elevated cTnT within 6 h of symptom was associated with a higher risk of adverse events compared with elevations after 6 h (OR 2.4 vs. 1.5). Conclusions Quantitative ST↓ and cTnT status are complementary in assessing risk among ACS patients and both should be employed to determine prognosis and assist in medical decision making.

To evaluate quantitative relationships between baseline Q-wave width and 90-day outcomes in ST-segment elevation myocardial infarction (STEMI).Baseline Q-waves are useful in predicting clinical outcomes after MI.3589 STEMI patients were assessed from a multi-centre study.1156 patients of the overall cohort had pathologic Q-waves. The 90-day mortality and the composite of mortality, congestive heart failure (CHF), or cardiogenic shock (p0.001 for both outcomes) rose as Q-wave width increased. After adapting a threshold ≥40ms for inferior and ≥20ms for lateral/apical MI in all patients (n=3065) with any measureable Q-wave we found hazard ratios (HR) for mortality (HR: 2.44, 95% confidence interval (CI) (1.54-3.85), p0.001) and the composite (HR: 2.32, 95% CI (1.70-3.16), p0.001). This improved reclassification of patients experiencing the composite endpoint versus the conventional definition (net reclassification index (NRI): 0.23, 95% CI (0.09-0.36), p0.001) and universal MI definition (NRI: 0.15, 95% CI (0.02-0.29), p=0.027).The width of the baseline Q-wave in STEMI adds prognostic value in predicting 90-day clinical outcomes. A threshold of ≥40ms in inferior and ≥20ms for lateral/apical MI enhances prognostic insight beyond current criteria.

Objectives Our objectives were to develop a risk-stratification model addressing the importance of the magnitude and distribution of ST segment depression in predicting long-term outcomes and to validate the model in an analogous patient population. Background Although patients without ST segment elevation presenting with acute coronary syndromes represent an increasingly frequent population admitted to coronary care units, little attention has been paid to quantifying their ST segment abnormalities. Methods ST segment depression was categorized into three groups: 1) no ST segment depression; 2) 1-mm ST segment depression in two contiguous leads; and 3) ST segment depression > or =2 mm in two contiguous leads. A logistic regression model was developed using Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON-A) data to assess the prognostic value of the extent and distribution of ST segment depression in predicting one-year mortality. The model was validated using the non-ST segment elevation population in Global Use of Strategies To Open occluded arteries in acute coronary syndromes (GUSTO-IIb). Results ST segment depression was the strongest predictor of one-year mortality, accounting for 35% of the model's predictive power. Patients with ST segment depression > or =2 mm were approximately 6 times (odds ratio [OR] 5.73, 95% confidence interval [CI] 2.8 to 11.6) more likely to die within one year than patients with no ST segment depression. On validation, the model showed good discriminatory power (c-index = 0.75). Patients with ST segment depression > or =2 mm in more than one region were almost 10 times more likely to die within one year than patients with no ST segment depression. Conclusions These data provide new evidence supporting the powerful prognostic value of the baseline electrocardiogram and, in particular, the magnitude and distribution of ST segment depression in predicting unfavorable events.

Background —Little information exists concerning practice patterns between Canada and the United States in the management of myocardial infarction (MI) patients without ST-segment elevation and unstable angina. Methods and Results —We examined the practice patterns and 1-year outcomes of 2250 US and 922 Canadian patients without ST-elevation acute coronary syndromes in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb trial. The US hospitals more commonly had on-site facilities for angiography and revascularization. These procedures were performed more often and sooner in the United States than Canada, whereas Canadian patients were more likely to undergo noninvasive stress testing. The length of initial hospital stay was 1 day longer for Canadian than US patients. Recurrent and refractory ischemia was more common in Canada. One-year mortality was comparable between the 2 countries. However, at 6 months, even after baseline differences were accounted for, the (re)MI rate was significantly higher in Canadian than US patients with unstable angina (8.8% versus 5.8%, P =0.039), as was the composite rate of death or (re)MI (13.1% versus 9.1%, P =0.016). Conclusions —One-year mortality was comparable between Canada and the United States in both MI and unstable angina cohorts despite higher intervention rates in the United States. However, outcomes at 6 months among patients with unstable angina differed. Whereas more frequent coronary interventions were not associated with reduced recurrent MI or death among MI patients without ST elevation, they may favorably affect outcomes in patients with unstable angina.

Background —Recurrent ischemia after an acute coronary syndrome portends an unfavorable outcome and has major resource-use implications. This issue has not been studied systematically among the spectrum of patients with acute coronary presentations, encompassing those with and without ST-segment elevation. Methods and Results —We assessed the 1-year prognosis of the 12 142 patients enrolled in the GUSTO-IIb trial by the presence (n=4125) or absence (n=8001) of ST-segment elevation. This latter group was further categorized into those with baseline myocardial infarction (n=3513) or unstable angina (n=4488). We also assessed the incidence of recurrent ischemia and its impact on outcomes. Recurrent ischemia was significantly rarer in those with ST-segment elevation (23%) than in those without (35%; P P Conclusions —Refractory ischemia was associated with an approximate doubling of mortality among patients with ST-segment elevation and a near tripling of risk among those without ST elevation. This study highlights not only the substantial increase in late mortality and reinfarction with non–ST-segment-elevation infarction but also the opportunities for better triage and application of therapeutic strategies for patients with recurrent ischemia.

Objective: We examined the response to hypertonic saline challenge (SC) as a potential predictor of fluid retention during heart failure induced by rapid ventricular pacing. Methods: Twelve dogs (22 ± 4 kg) were given an intra-arterial bolus of 30 ml of 20% saline after establishing baseline fluid intake and urine output (24 h). Dogs were classified according to whether they drank more (Group A) or less (Group B) than the amount required to dilute the SC to isotonicity. Fluid retention was then assessed during heart failure after rapid ventricular pacing according to a graded ordinal scale and correlated with the responses to SC. Results: No difference was noted in baseline fluid intake (1112 ± 236 ml in Group A vs. 809 ± 129 ml in Group B). Five hours after SC cumulative water intake was significantly greater in Group A than in Group B (1018 ± 136 vs. 591 ± 17 ml) ( P < 0.01). Urine sodium concentration was 113 ± 11 and 124 ± 28 mmol/l at baseline in Group A and B, respectively; increased to 190 ± 21 and 295 ± 59 mmol/l at 5 h and remained elevated 24 h after SC, 177 ± 60 and 274 ± 55 mmol/l (both P < 0.01 for within-group comparisons vs. baseline). Urine sodium concentration was less in Group A than in Group B at 5 and 24 h ( P < 0.05). The fluid retention score was greater in Group A (3.6 ± 0.5) than in Group B (0.8 ± 0.4) ( P < 0.01). Fluid retention in heart failure correlated with water intake after the pre-pacing SC ( r = 0.68, P < 0.025) and inversely with urine concentrating ability ( r = −0.58, P < 0.02). Furthermore, water intake and urine concentrating ability following the SC were inversely related ( r = −0.67, P < 0.02). Conclusions: We conclude that normal dogs may be classified according to their fluid intake after SC. Those dogs that drank excessively and produced a dilute urine were more likely to retain fluid during pacing-induced heart failure. Hence, fluid intake and the ability to excrete a concentrated urine after a saline challenge may be useful variables to predict fluid retention in pacing-induced heart failure.

There is conflicting evidence with regard to the value of electrocardiographic left ventricular hypertrophy (LVH) in myocardial infarction. Of 5,951 patients in the ASSENT-3 trial, 273 (5%) had LVH on baseline electrocardiograms and had significantly higher mortality rates at 30 days (11% vs 6%, p = 0.001) and 1 year (13% vs 8%, p = 0.007). After adjustment for differences in baseline parameters, LVH remained an independent predictor of 30-day (hazard ratio 2.3, 95% confidence interval 1.4 to 3.9) and 1-year (hazard ratio 1.8, 95% confidence interval 1.1 to 2.8) mortality rates. Thus, electrocardiographic LVH is a prognostic tool in identifying short- and long-term mortality rates in patients who have ST-elevation myocardial infarction and receive fibrinolysis.

Aims To examine the incidence of and propensity for non-culprit interventions performed at the time of the primary percutaneous coronary intervention (PCI) and its association with 90-day outcomes. Methods and results We examined the incidence, propensity for, and associated 90-day outcomes following non-culprit interventions performed at the time of primary PCI among ST-elevation myocardial infarction patients with multi-vessel coronary artery disease (MVD). Of the 5373 patients who underwent primary PCI in the APEX-AMI trial, 2201 had MVD. Of those, 217 (9.9%) underwent non-infarct-related arteries (IRA) PCI, whereas 1984 (90.1%) underwent PCI of the IRA alone. Ninety-day death and death/CHF/shock were higher in the non-IRA group compared with the IRA-only PCI group (12.5 vs. 5.6%, P (log-rank) < 0.001 and 17.4 vs. 12.0%, P (log-rank) = 0.020, respectively). After adjusting for patient and procedural characteristics as well as propensity for performing non-IRA PCI, this procedure remained independently associated with an increased hazard of 90-day mortality [adjusted hazard ratio 2.44, 95% CI (1.55–3.83), P < 0.001]. Conclusion Non-culprit coronary interventions were performed at the time of primary PCI in 10% of MVD patients and were significantly associated with increased mortality. Our data support current guideline recommendations discouraging the performance of such procedures in stable primary PCI patients. Prospective randomized study of this issue may be warranted.

The prognostic value of myocardial infarct size estimation by QRS scoring in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI) is unclear. The standard 32-point Selvester QRS score on the discharge electrocardiogram (each point approximately 3% left ventricular mass) was calculated in 4,113 patients with STEMI who underwent primary PCI and survived to hospital discharge in the APEX-AMI trial. QRS scores were divided into tertiles, i.e.,or =3 (10% myocardium), 4 to 7 (10% to 21% myocardium), andor =8 (21% myocardium). Adjusted associations between QRS score and 90-day outcomes (death and composite of death/congestive heart failure (CHF)/shock) were examined. Higher QRS scores were associated with male gender, higher heart rate, worse Killip class, noninferior infarct location, greater ST-segment deviation, and longer times to reperfusion. Higher QRS scores were also associated with impaired culprit artery flow before and after PCI and more frequent multivessel disease. Adverse outcomes occurred more often in patients with higher QRS scores (90-day death: 1.9%, QRS score 0 to 3; 3.4%, 4 to 7; 4.9%,or =8; 90-day death/shock/CHF: 4.5%, 0-3; 7.8%, 4 to 7; 12.1%,or =8). After multivariable adjustment, patients with higher QRS scores remained more likely to develop an adverse outcome versus those with QRS scoresor =3 (score 4 to 7, hazard ratios [HR] for death 2.08, 95% confidence interval [CI] 1.26 to 3.41; HR for death/CHF/shock 2.00, 95% CI 1.26 to 3.17; scoreor =8, HR for death 2.57, 95% CI 1.56 to 4.24, HR for death/CHF/shock 2.93, 95% CI 1.84 to 4.67). In conclusion, infarct size as estimated by QRS scoring at hospital discharge is an independent and prognostically relevant metric in patients with STEMI undergoing primary PCI.

Background Atrial infarction reportedly occurs in 0.7% to 52% of ST-elevation myocardial infarctions (STEMIs), up to two thirds of whom develop atrial fibrillation and flutter (AF). Prospective validation of electrocardiographic atrial infarction patterns is lacking. Hence, in STEMI patients treated with primary percutaneous coronary intervention, we examined whether baseline atrial electrocardiographic changes or atrial infarction patterns predicted new AF or mortality. Methods Within the Assessment of Pexelizumab in Acute Myocardial Infarction trial, a nested case-control study was conducted. Patients with new AF were matched 1:1 with controls, and baseline atrial electrocardiographic variables were examined. Results Abnormal P wave morphology (Liu minor criterion for atrial infarction) was significantly associated with new AF (adjusted odds ratio, 1.68; 1.03-2.73). This was also independently associated with 90-day mortality in the overall case-control cohort (adjusted hazard rate, 1.90; 1.04-3.46) and among patient with new-onset AF (adjusted hazard rate, 2.43; 1.22-4.84). Conclusions Abnormal P wave morphology significantly predicted new AF and 90-day mortality in STEMI patients.

Background— Primary percutaneous coronary angioplasty is an effective and widely adopted treatment for acute myocardial infarction. A simple method of determining prognosis after primary percutaneous coronary intervention (PCI) would facilitate appropriate care and expedite hospital discharge. Thus, we determined the prognostic importance of various measures of ST-segment–elevation recovery after primary PCI in a large, contemporary cohort of patients with ST-elevation myocardial infarction. Methods and Results— We analyzed ECG data describing the magnitude and extent of ST-segment elevation and deviation before and early after (ie, 30 minutes) primary PCI in the study cohort of 4866 subjects with electrocardiographically high-risk ST-elevation myocardial infarction enrolled in the Assessment of PEXelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Associations among 6 methods for calculating ST-segment recovery, biomarker estimates of infarct size (ie, peak creatine kinase, creatine kinase-MB, and troponin I and T), and prespecified clinical outcomes (ie, rates of 90-day death and 90-day death, heart failure, or shock) were examined. All ST-segment–recovery methods provided strong prognostic information regarding clinical outcomes. A simple ST-segment–recovery method of residual ST-segment elevation measurement in the most affected lead on the post-PCI ECG performed as well as complex methods that required comparison of pre- and post-PCI ECGs or calculation of summed ST-segment deviation in multiple leads (ie, worst-lead residual ST elevation: adjusted hazard ratio for 90-day death rate [reference Conclusions— An ECG performed early after primary PCI is a simple, widely available, inexpensive, and powerful prognostic tool applicable to patients with ST-elevation myocardial infarction.

Aims Patients in ASSENT-4 PCI undergoing tenecteplase-facilitated percutaneous coronary intervention (PCI) had more adverse events than those undergoing primary PCI. We analysed this to gain further insights. Methods and results A total of 549 patients with facilitated PCI and 541 undergoing primary PCI were characterized according to the extent of ST resolution. We also examined the relationship between time from symptom onset, presence of baseline Q waves, and 90 day events. Irrespective of treatment, 90 day mortality was lowest among 186 patients with complete ST resolution at both 60 and 180 min (1.8% facilitated; 0% primary PCI group) and highest in those 502 patients without complete ST resolution at either 60 or 180 min (6.7% facilitated; 5.2% primary PCI group, all P ≤ 0.05). Patients undergoing facilitated PCI presenting >3 h with baseline Q waves also had higher 90 day mortality compared with those without Q waves (10.4 vs. 2.5%, P = 0.056). No significant differences were found within primary PCI patients on the basis of time from symptom onset or presence of initial Q waves. Conclusion In this post hoc analysis, our data suggest that a fibrinolysis-facilitated PCI strategy was especially harmful in patients presenting beyond 3 h from symptom onset with established Q waves on their baseline ECG. This may relate to the convergence of later, less effective pre-procedural reperfusion but persisting exposure to the pro-thrombotic and bleeding risks of fibrinolysis.

Introduction Spontaneous reperfusion (SR) in ST-elevation myocardial infarction has traditionally been assessed by coronary angiography. The frequency of SR varies widely in prior studies, and the clinical implications in the modern reperfusion era are unclear. Accordingly, using data from the ASSENT 4 PCI (ASsessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention) study, we undertook a systematic assessment of SR using both electrocardiographic (ECG) and angiographic techniques. Methods and Results Five hundred eighty-five patients randomized to the primary percutaneous coronary intervention (PCI) arm of ASSENT 4 PCI were studied: all had ECG and thrombolysis in myocardial infarction flow data available approximately 60 minutes after randomization and before PCI. Electrocardiographic SR (≥70% ST-segment resolution) occurred in 14.9% (87/585) and angiographic SR (thrombolysis in myocardial infarction grade 3) in 14.7% (86/585) of patients. Thirty-day clinical outcomes of patients with ECG SR versus no ECG SR tended to have lower mortality (0% vs 3.4%, P = .091), a lower composite of death/shock/congestive heart failure (6.9% vs 12.2%, P = .148), and significant reductions in death/reinfarction (0% vs 5.6%, P = .014). By contrast, no such differences were evident in patients with angiographic SR versus no SR for death (2.3% vs 3.0%, P = 1.00), death/shock/congestive heart failure (9.3% vs 11.8%, P = .498), or death/reinfarction (2.3% vs 5.2%, P = .409). Conclusions Whereas the frequency of SR was comparable using either ECG or angiographic criteria, clinical outcomes were best aligned with ECG SR. These data support the role of the ECG in assessing reperfusion and likely reflect the overall impact of myocardial perfusion versus infarct-related artery epicardial patency alone.

Udgivelsesdato: 2009-Jan-15 Acute ST-segment elevation myocardial infarction requires prompt restoration of myocardial perfusion to salvage myocardium at risk of ischemic necrosis and improve clinical outcome. Early resolution of ST-segment elevation during the time after reperfusion has been associated with both these end points. From the ASsessment of the Safety and Efficacy of a New Thrombolytic regimen (ASSENT) 3 trial, 3,425 patients were analyzed to investigate whether the amount of ST-segment resolution, divided into 3 groups (complete, >70%; partial, 30% to 70%; and no resolution, 5 times the upper reference level at 50.3%, 71.8%, and 76.3%, respectively. In conclusion, our findings supported previous smaller studies suggesting that early resolution of ST elevation, as a sign of early myocardial reperfusion, resulted in less myocardial damage and preservation of left ventricular function.

Aims To examine the extent and impact on clinical outcomes of adherence to electrocardiogram (ECG) entry criteria in ST-elevation myocardial infarction patients in the assessment of pexelizumab in acute myocardial infarction (APEX-AMI) trial. Methods and results We examined the frequency, characteristics, and outcomes of patients enrolled in APEX-AMI trial who did not meet the trial ECG entry criteria. Among 5615 patients analysed, 28.8% did not meet ECG entry criteria: this occurred more than twice as frequently amongst those with high-risk inferior vs. those with other MI (42.3 vs. 19.3%, P < 0.001). Regardless of infarct location, patients who failed to meet ECG entry criteria had significantly lower mortality (2.5 vs. 4.5% at 30 days and 3.1 vs. 5.3% at 90 days; both P < 0.001) and the composite rate of death, cardiogenic shock, or CHF (5.8 vs. 10.3% at 30 days and 6.9 vs. 11.4% at 90 days; both P < 0.001) as compared to those who met criteria. Conclusion In APEX-AMI over one-quarter of enrolled patients did not meet ECG entry criteria and had better outcomes than eligible patients. Although the trial’s primary result was unaffected by alignment with the baseline ECG criteria, our findings may have important implications in designing future trials.

Aims To demonstrate the feasibility and clinical utility of developing dynamic risk assessment models for ST-segment elevation myocardial infarction (STEMI) patients. Methods and results In 6066 STEMI patients enrolled in the Assessment of the Safety and Efficacy of a New Thrombolytic-3 (ASSENT-3) trial with complete electrocardiographic data, we assessed the probability of 30-day mortality over the following forecasting periods beginning at day 0 (baseline), 3 h, day 2, and day 5 using multiple-logistic regression. These models were validated and simplified in independent samples of 1622 similar fibrinolytic-treated patients from the ASSENT-3 PLUS trial and in 814 STEMI patients undergoing primary percutaneous coronary intervention in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial. The discriminatory power of these predictive models, from baseline to day 5, was excellent (c-statistics 0.80 to 0.87); and their predictive ability was supported by strong gradients in mortality outcomes as the risk score increased. Dynamic modelling also provided information on the change in prognosis over time which may be used to advise more appropriate therapeutic decisions, e.g. the identification of high-risk patients for possible co-interventions. Conclusion Dynamic modelling for STEMI patients enhances the risk assessment and stratification and should provide valuable ongoing guidance for their management.

Objectives: To examine the interaction between ST segment depression on the baseline ECG and subsequent in-hospital revascularisation on six month mortality among patients with non-ST elevation acute coronary syndromes. To examine whether ST segment depression influenced clinical decision making and whether there was international variation in the use of cardiac procedures across ST segment depression categories. Methods: 11 453 patients enrolled in GUSTO-IIB (global use of strategies to open occluded coronary arteries), PARAGON (platelet IIb/IIIa antagonism for the reduction of acute coronary syndrome events in a global organisation network) -A, and PARAGON-B were studied. Patients were categorised as having no ST segment depression, 1 mm ST segment depression in two contiguous leads, and ST segment depression ⩾ 2 mm in two contiguous leads. International practice across four geographic regions was examined: USA, Canada, Europe, and Australia/New Zealand. Results: Revascularisation appeared to have no impact on survival among patients with no ST segment depression; however, revascularisation was associated with a significant survival benefit among patients with ST segment depression ⩾ 1 mm. There was an inverse relation between the extent of ST segment depression and the use of angiography as well as angioplasty (p Conclusions: International practice patterns in procedure use appear to be insensitive to the extent of ST segment depression. Major opportunities for more efficient delivery of care exist in all regions.