A second shell residue modulates a conserved ATP-binding site with radically different affinities for ATP.

BACKGROUND: Prediction of ligand binding and design of new function in enzymes is a time-consuming and expensive process. Crystallography gives the impression that proteins adopt a fixed shape, yet enzymes are functionally dynamic. Molecular dynamics offers the possibility of probing protein movement while predicting ligand binding. Accordingly, we choose the bacterial F1Fo ATP synthase ε subunit to unravel why ATP affinity by ε subunits from Bacillus subtilis and Bacillus PS3 differs ~500-fold, despite sharing identical sequences at the ATP-binding site. METHODS: We first used the Bacillus PS3 ε subunit structure to model the B. subtilis ε subunit structure and used this to explore the utility of molecular dynamics (MD) simulations to predict the influence of residues outside the ATP binding site. To verify the MD predictions, point mutants were made and ATP binding studies were employed. RESULTS: MD simulations predicted that E102 in the B. subtilis ε subunit, outside of the ATP binding site, influences ATP binding affinity. Engineering E102 to alanine or arginine revealed a ~10 or ~54 fold increase in ATP binding, respectively, confirming the MD prediction that E102 drastically influences ATP binding affinity. CONCLUSIONS: These findings reveal how MD can predict how changes in the "second shell" residues around substrate binding sites influence affinity in simple protein structures. Our results reveal why seemingly identical ε subunits in different ATP synthases have radically different ATP binding affinities. GENERAL SIGNIFICANCE: This study may lead to greater utility of molecular dynamics as a tool for protein design and exploration of protein design and function.

Gender-Specific Differences in All-Cause Mortality Between Incomplete and Complete Revascularization in Patients With ST-Elevation Myocardial Infarction and Multi-Vessel Coronary Artery Disease.

The best revascularization strategy (complete vs incomplete revascularization) in patients with ST-elevation myocardial infarction (STEMI) is still debated. The interaction between gender and revascularization strategy in patients with STEMI on all-cause mortality is uncertain. The aim of the present study was to evaluate gender-specific difference in all-cause mortality between incomplete and complete revascularization in patients with STEMI and multi-vessel coronary artery disease. The study population consisted of 375 men and 115 women with a first STEMI and multi-vessel coronary artery disease without cardiogenic shock at admission or left main stenosis. The 30-day and 5-year all-cause mortality was examined in patients categorized according to gender and revascularization strategy (incomplete and complete revascularization). Within the first 30 days, men and women with incomplete revascularization were associated with higher mortality rates compared with men with complete revascularization. However, the gender-strategy interaction variable was not independently associated with 30-day mortality after STEMI when corrected for baseline characteristics and angiographic features. Within the survivors of the first 30 days, men with incomplete revascularization (compared with men with complete revascularization) were independently associated with all-cause mortality during 5 years of follow-up (hazard ratios 3.07, 95% confidence interval 1.24;7.61, p = 0.016). In contrast, women with incomplete revascularization were not independently associated with 5-year all-cause mortality (hazard ratios 0.60, 95% confidence interval 0.14;2.51, p = 0.48). In conclusion, no gender-strategy differences occurred in all-cause mortality within 30 days after STEMI. However, in the survivors of the first 30 days, incomplete revascularization in men was independently associated with all-cause mortality during 5-year follow-up, but this was not the case in women.

Prognosis of complete versus incomplete revascularisation of patients with STEMI with multivessel coronary artery disease: an observational study.

OBJECTIVE: The best strategy in patients with acute ST-segment elevation myocardial infarction (STEMI) with multivessel coronary artery disease (CAD) regarding completeness of revascularisation of the non-culprit lesion(s) is still unclear. To establish which strategy should be followed, survival rates over a longer period should be evaluated. The aim of this study was to investigate whether complete revascularisation, compared with incomplete revascularisation, is associated with reduced short-term and long-term all-cause mortality in patients with first STEMI and multivessel CAD. METHODS: This retrospective study consisted of 518 patients with first STEMI with multivessel CAD. Complete revascularisation (45%) was defined as the treatment of any significant coronary artery stenosis (≥70% luminal narrowing) during primary or staged percutaneous coronary intervention prior to discharge. The primary end point was all-cause mortality. RESULTS: Incomplete revascularisation was not independently associated with 30-day all-cause mortality in patients with acute first STEMI and multivessel CAD (OR 1.98; 95% CI 0.62to6.37; p=0.25). During a median long-term follow-up of 6.7 years, patients with STEMI with multivessel CAD and incomplete revascularisation showed higher mortality rates compared with patients who received complete revascularisation (24% vs 12%, p<0.001), and these differences remained after excluding the first 30 days. However, in multivariate analysis, incomplete revascularisation was not independently associated with increased all-cause mortality during long-term follow-up in the group of patients with STEMI who survived the first 30 days post-STEMI (HR 1.53 95% CI 0.89-2.61, p=0.12). CONCLUSION: In patients with acute first STEMI and multivessel CAD, incomplete revascularisation compared with complete revascularisation was not independently associated with increased short-term and long-term all-cause mortality.

Influence of coronary vessel dominance on short- and long-term outcome in patients after ST-segment elevation myocardial infarction.

AIMS: Prognostic importance of coronary vessel dominance in patients with ST-elevation myocardial infarction (STEMI) remains uncertain. The aim of this study was to assess influence of coronary vessel dominance on the short- and long-term outcome after STEMI. METHODS AND RESULTS: Coronary angiographic images of consecutive patients presenting with first STEMI were retrospectively reviewed to assess coronary vessel dominance. Patients were followed after STEMI during a median period of 48 (IQR38-61) months for the occurrence of all-cause mortality and the composite of reinfarction and cardiac death. The population comprised 1131 patients of which 971 (86%) patients had a right dominant, 102 (9%) a left dominant, and 58 (5%) a balanced system. After 5 years of follow-up, the cumulative incidence of all-cause mortality was significantly higher in patients with a left dominant system, compared with a right dominant and balanced system (log-rank P = 0.013). Moreover, a left dominant system was an independent predictor for 30-day mortality (OR 2.51, 95% CI 1.11-5.67, P = 0.027) and the composite of reinfarction and cardiac death within 30-days after STEMI (OR 2.25, 95% CI 1.09-4.61, P = 0.028). In patients surviving first 30-days post-STEMI, coronary vessel dominance had no influence on long-term outcome. CONCLUSIONS: A left dominant coronary artery system is associated with a significantly increased risk of 30-day mortality and early reinfarction after STEMI. After surviving the first 30-days post-STEMI, coronary vessel dominance had no influence on long-term outcome.

Relation between coronary arterial dominance and left ventricular ejection fraction after ST-segment elevation acute myocardial infarction in patients having percutaneous coronary intervention.

The presence of a left dominant coronary artery system is associated with worse outcome after ST-segment elevation myocardial infarction (STEMI) compared with right dominance or a balanced coronary artery system. However, the association between coronary arterial dominance and left ventricular (LV) function at follow-up after STEMI is unclear. The present study aimed at evaluating the relation between coronary arterial dominance and LV ejection fraction (LVEF) shortly after STEMI and at 12-month follow-up. A total of 741 patients with STEMI (mean age 60 ± 11 years and 77% men) were evaluated with 2-dimentional echocardiography within 48 hours of admission (baseline) and at 12-month follow-up after STEMI. Coronary arterial dominance was assessed on the angiographic images obtained during primary percutaneous coronary intervention. A right, left, and balanced dominant coronary artery system was noted in 640 (86%), 58 (8%), and 43 (6%) patients, respectively. At baseline, significant difference in LV function was observed, with slightly lower LVEF in patients with a left dominant coronary artery system (LVEF 45 ± 8% vs 48 ± 9% and 50 ± 9%, for left dominant, right dominant, and balanced coronary artery system respectively, p = 0.03). However, at 12-month follow-up no differences in LV function or volumes were observed among the different coronary arterial dominance groups. In conclusion, patients with a left dominant coronary artery system had lower LVEF early after STEMI. At 12-month follow-up, differences in LVEF were no longer present among the different coronary arterial dominance groups.

Impact of hypertension on clinical outcome in STEMI patients undergoing primary angioplasty with BMS or DES: insights from the DESERT cooperation.

BACKGROUND: Hypertension is a well known risk factor for atherosclerosis. However, data on the prognostic impact of hypertension in patients with ST elevation myocardial infarction (STEMI) are inconsistent and mainly related to studies performed in the thrombolytic era, with very few data in patients undergoing primary angioplasty. Therefore, the aim of the current study was to evaluate the impact hypertension on clinical outcome in STEMI patients undergoing primary PCI with BMS or DES. METHODS: Our population is represented by 6298 STEMI patients undergoing primary angioplasty included in the DESERT database from 11 randomized trials comparing DES vs BMS for STEMI. RESULTS: Hypertension was observed in 2764 patients (43.9%), and associated with ageing (p<0.0001), female gender (p<0.001), diabetes (p<0.0001), hypercholesterolemia (p<0.0001), previous MI (p=0.002), previous revascularization (p=0.002), longer time-to-treatment (p<0.001), preprocedural TIMI 3 flow, and with a lower prevalence of smoking (41% vs 53.9%, p<0.001) and anterior MI (42% vs 45.9%, p=0.002). Hypertension was associated with impaired postprocedural TIMI 0-2 flow (Adjusted OR [95% CI]=1.22 [1.01-1.47], p=0.034). At a follow-up of 1,201 ± 440 days, hypertension was associated with higher mortality (adjusted HR [95% CI]=1.24 [1.01-1.54], p=0.048), reinfarction (adjusted HR [95% CI]=1.31 [1.03-1.66], p=0.027), stent thrombosis (adjusted HR [95% CI]=1.29 [0.98-1.71], p=0.068) and TVR (adjusted HR [95% CI]=1.22 [1.04-1.44], p=0.013). CONCLUSIONS: This study showed that among STEMI patients undergoing primary angioplasty with DES or BMS, hypertension is independently associated with impaired epicardial reperfusion, mortality, reinfarction and TVR, and a trend in higher ST.

Drug-eluting stents in patients with anterior STEMI undergoing primary angioplasty: a substudy of the DESERT cooperation.

BACKGROUND: Several concerns have emerged on the higher risk of in-stent thrombosis after drug-eluting stent (DES) implantation, especially in the setting of STEMI patients. Few data have even been reported in high-risk patients, such as those with anterior MI. Therefore this represents the aim of the current study. METHODS: The literature was scanned by formal searches of electronic databases (MEDLINE and CENTRAL). We examined all completed randomized trials of DES for STEMI. The following key words were used for study selection: randomized trial, myocardial infarction, reperfusion, primary angioplasty, stenting, DES, sirolimus-eluting stent (SES), Cypher, paclitaxel-eluting stent (PES), Taxus. No language restrictions were enforced. RESULTS: Individual patient's data were obtained from 11 out of 13 trials, including a total of 2,782 patients with anterior MI [1,739 or 62.5% randomized to DES and 1,043 or 37.5% randomized to bare-metal stent (BMS)]. At long-term follow-up, no significant benefit was observed with DES as compared to BMS in terms of mortality [9.8 vs 10.9%, HR (95% CI) = 0.81 (0.61, 1.07), p = 0.13, p heterogeneity = 0.18], reinfarction [8.8 vs 6.4%, respectively; HR (95% CI) = 1.14 (0.80, 1.61), p = 0.47, p heterogeneity = 0.82], and stent thrombosis [5.6 vs 5%, OR (95% CI) = 0.88 (0.59, 1.30), p = 0.51, p heterogeneity = 0.65], whereas DES was associated with a significant reduction in terms of target-vessel revascularization (TVR) [13.7 vs 23.4%; OR (95% CI) = 0.56 (0.46, 0.69), p < 0.0001, p het = 0.81] that was observed at both early (within 1 year) [7 vs 14.7%, HR (95% CI) = 0.56 (0.46, 0.69), p < 0.0001, p het = 0.81] and late (>1 year) follow-up [7.2 vs 9%, HR (95% CI) = 0.67 (0.47, 0.96), p = 0.03, p het = 0.96]. CONCLUSIONS: This study showed that among patients with anterior STEMI undergoing primary angioplasty, SES and PES, as compared to BMS, are associated with a significant reduction in TVR at long-term follow-up. No concerns were found with the use of first-generation DES in terms of mortality.

Outcome after ST elevation myocardial infarction in patients with cancer treated with primary percutaneous coronary intervention.

The simultaneous occurrence of cancer and coronary heart disease is increasing in the Western world. Nevertheless, the influence of cancer on ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) has not been investigated extensively. This multicenter registry included patients with STEMI treated with primary PCI from 2006 to 2009. Patients were stratified according to history of cancer, and primary focus lay on all-cause and cardiac mortalities during 1-year follow-up. Adjusted effect sizes were calculated using Cox proportional hazard models. In total, 208 patients had a history of cancer (diagnosed ≤6 months ago in 20.7%, 6 months to 3 years ago in 21.7%, and >3 years ago in 57.6%) and 3,215 patients had no history of cancer. Chemotherapy had been administered previously to 23% of patients with cancer. Patients with cancer were older, more frequently women, and more commonly known with previous myocardial infarction or anemia. Reperfusion rates were similar after PCI. Patients with cancer showed greater all-cause (17.4% vs 6.5% in other patients) and cardiac mortalities at 1 year (10.7% vs 5.4% in other patients) because of high early cardiac death (23.8%) in recently diagnosed patients with cancer. After adjustment, a recent cancer diagnosis predicted cardiac mortality at 7 days (hazard ratio 3.34, 95% confidence interval 1.57 to 7.08). The adverse prognosis was partly explained by anemia and occurrence of cardiogenic shock, whereas outcome was independent of cancer treatment. In conclusion, patients with cancer showed greater mortality after STEMI. A cancer diagnosis in the 6 months before primary PCI was strongly associated with early cardiac mortality.

In-hospital major bleeding and its clinical relevance in patients with ST elevation myocardial infarction treated with primary percutaneous coronary intervention.

Advances in antithrombotic therapy for ST elevation myocardial infarction (STEMI) enhance the risk of bleeding. Therefore, the incidence, determinants, and prognostic implications of in-hospital major bleeding after primary percutaneous coronary intervention for STEMI were investigated. In 963 consecutive patients, the incidence of bleeding was evaluated according to commonly used classifications including Can Rapid risk stratification of Unstable angina patients Suppress Adverse outcomes with Early implementation of the ACC/AHA guidelines, Thrombolysis In Myocardial Infarction, Global Use of Strategies To Open coronary arteries, and Bleeding Academic Research Consortium. Multivariate regression analyses investigated determinants of bleeding and the relation between bleeding and 1-year all-cause mortality. Large variability in incidence existed depending on classification (1.3% to 21%). Female gender, heart rate, creatinine, multivessel disease, cardiogenic shock, and procedural failure were independently associated with bleeding. One-year mortality reached 10.2% in bleeders versus 2.0% in nonbleeders (p <0.001). Bleeding was independently associated with an increased risk of 1-year mortality (hazard ratio [HR] 2.41, p <0.017). Assessment of individual classifications confirmed the increased risk of mortality for Bleeding Academic Research Consortium (HR 2.27, p = 0.048), but not for Can Rapid risk stratification of Unstable angina patients Suppress Adverse outcomes with Early implementation of the ACC/AHA guidelines, Thrombolysis In Myocardial Infarction, and Global Use of Strategies To Open coronary arteries bleeding. Thrombotic events occurred more frequently in bleeders (5.8% vs 1.5%, p <0.001); however, bleeding remained independently related to mortality with a negligible reduction in HR (2.25, p = 0.028) after adjustment. In conclusion, in-hospital major bleeding was frequently observed after STEMI, but a widespread variation in incidence existed depending on the applied definition. Patient and procedural characteristics were related to bleeding, allowing identification of high-risk patients. In-hospital major bleeding was independently associated with 1-year all-cause mortality; however, not all bleeding classifications proved equally relevant to prognosis. The relation between bleeding and mortality was shown not to be driven by the higher rate of thrombotic events among bleeders.

Time course, predictors and clinical implications of stent thrombosis following primary angioplasty. Insights from the DESERT cooperation.

Primary percutaneous coronary intervention (pPCI) has improved survival as compared to thrombolysis. Concerns still remain regarding the risk of stent thrombosis in the setting of STEMI, especially after drug-eluting stent (DES) implantation. Therefore, the aim of this study was to report on the timing of stent thrombosis (ST) with both DES and bare metal stents (BMS) and its prognostic significance in patients undergoing pPCI. The Drug-Eluting Stent in Primary Angioplasty (DESERT) cooperation is based on a pooled database including individual data of randomised trials that evaluate the long-term safety and effectiveness of DES as compared to BMS in patients undergoing pPCI for STEMI. Follow-up data were collected for 3-6 years after the procedure. ST was defined as definite or probable, based on the ARC definition. The study population consists of 6,274 STEMI patients undergoing primary angioplasty with BMS or DES. At 1201 ± 440 days, ST occurred in 267 patients (4.25%). Most of the events were acute or subacute (within 30 days) and very late (> 1 years), with different distribution between DES vs BMS. Patients with ST were more often diabetic (21.7% vs 15.1%, p=0.005), more frequently had post-procedural TIMI 0-2 flow (14.0% vs 9.3%, p = 0.01), and were less often treated with dual antiplatelet therapy at one year follow-up. Diabetes (p = 0.036), post-procedural TIMI 0-2 Flow (p = 0.013) and ischaemia time > 6 hours (p = 0.03) were independent predictors of ST. Post-procedural TIMI 0-2 flow (p = 0.001) and ischaemia time > 6 hours (p < 0.001) were independent predictors of early ST, ischaemia time > 6 hours (p = 0.05) was independent predictor of late ST, whereas diabetes (p = 0.022) and use of DES (p = 0.002) were independent predictors of very late ST. ST was associated with a significantly higher mortality (23.6% vs 6%, p < 0.001). The greatest impact on mortality was observed with subacute (40.4%) and late (20.9%) ST, as compared to acute (12.5%) and very late (9.1%) ST. ST was an independent predictor of mortality (HR [95%CI] = 3.73 [2.75-5.07], p < 0.001). In conclusion, ST occurs relatively frequently also beyond the first year for up to six years after pPCI in STEMI, with higher late occurrence rates among patients treated with first generation DES. ST after pPCI is a powerful predictor of mortality, especially subacute ST.

Impact of age on long-term outcome after primary angioplasty with bare-metal or drug-eluting stent (from the DESERT cooperation).

Despite mechanical reperfusion, elderly patients with ST-segment elevation myocardial infarction (STEMI) still experience unsatisfactory outcomes. Drug-eluting stents (DES) have significantly reduced target-vessel revascularization (TVR), but concerns have emerged about the higher risk of late stent thrombosis, which may be more pronounced in elderly patients. Therefore, the aim of this study was to evaluate the impact of age on outcome in patients with STEMI who underwent primary angioplasty with bare-metal stents (BMS) or DES. Our population comprised 6,298 patients who underwent primary angioplasty and stent implantation included in the Drug-Eluting Stent in Primary Angioplasty (DESERT) Cooperation database. Age was significantly associated with female gender (p <0.001), diabetes (p <0.001), hypertension (p <0.001), previous myocardial infarction (MI; p <0.001), ischemia time (p <0.001), and anterior MI (p <0.001) but inversely related to smoking (p <0.001). Elderly patients most often had infarct-related artery located in the descending artery (p = 0.014) and impaired postprocedural thrombolysis in myocardial infarction flow (p <0.001). Elderly patients were less often on clopidogrel at follow-up. At long-term follow-up, age was associated with a higher rate of death (hazard ratio [95% confidence interval] = 2.17 [1.97 to 2.39], p <0.0001), whereas no impact was observed on reinfarction (p = 0.36), stent thrombosis (p = 0.84), and TVR (p = 0.54). These results were confirmed in patients receiving both BMS and DES. The impact of age on mortality was confirmed after correction for baseline confounding factors (gender, diabetes hypertension, hypercholesterolemia, smoking, ischemia time, anterior MI, infarct-related artery location, and postprocedural thrombolysis in myocardial infarction 3 flow; adjusted hazard ratio [95% confidence interval] = 2.13 [1.78 to 2.56], p <0.001). In conclusion, this study shows that in patients with STEMI who underwent primary angioplasty, age is independently associated with higher mortality, observed with both BMS and DES, whereas no impact was observed on the rate of reinfarction, stent thrombosis, and TVR.

Peak and fixed-time high-sensitive troponin for prediction of infarct size, impaired left ventricular function, and adverse outcomes in patients with first ST-segment elevation myocardial infarction receiving percutaneous coronary intervention.

The clinical use of advanced imaging modalities for early determination of infarct size and prognosis is limited. As a specific indicator of myocardial necrosis, cardiac troponin T (cTnT) can be used as a surrogate measure for this purpose. The present study sought to investigate the use of peak and serial 6-hour fixed-time high-sensitive (hs) cTnT for estimation of infarct size, left ventricular (LV) function, and prognosis in consecutive patients with ST-segment elevation myocardial infarction. The infarct size was expressed as the 48-hour cumulative creatine kinase release. LV function at 3 months was assessed using the echocardiographic wall motion score index and LV ejection fraction using radionuclide ventriculography. Adverse outcomes, comprising all-cause death, implantable cardioverter-defibrillator implantation, or hospitalization for heart failure, were recorded at 1 year of follow-up. In 188 patients, the peak and all fixed-time values correlated significantly with the 48-hour cumulative creatine kinase release, wall motion score index, and LV ejection fraction. The hs-cTnT value at 24 hours demonstrated the greatest correlation (r = 0.86, r = 0.47, and r = -0.59, respectively; p <0.001 for all). In the multivariate regression models adjusted for the clinical parameters, almost all were independently associated with the 48-hour cumulative creatine kinase release, wall motion score index, and LV ejection fraction, with the hs-cTnT value at 24 hours having the largest effect. Moreover, all cTnT values independently predicted adverse outcomes, again, with the hs-cTnT value at 24 hours showing the largest influence (hazard ratio 3.77, 95% confidence interval 2.12 to 6.73, p <0.001). In conclusion, not only peak, but all fixed-time hs-cTnT values were associated with infarct size, LV function at 3 months, and adverse outcomes 1 year after ST-segment elevation myocardial infarction. The value 24 hours after the onset of symptoms had the closest associations with all outcomes. Therefore, serial sampling for a peak value might be redundant.

Meta-analysis comparing efficacy and safety of first generation drug-eluting stents to bare-metal stents in patients with diabetes mellitus undergoing primary percutaneous coronary intervention.

Several concerns have emerged regarding the higher risk for stent thrombosis (ST) after drug-eluting stent (DES) implantation, especially in the setting of ST-segment elevation myocardial infarction (STEMI). Few data have been reported so far in patients with diabetes mellitus, which is associated with high rates of target vessel revascularization after bare-metal stent (BMS) implantation but also higher rates of ST after DES implantation. Therefore, the aim of this study was to perform a meta-analysis of individual patients' data to evaluate the long-term safety and effectiveness of DES compared with BMS in patients with diabetes who undergo primary percutaneous coronary intervention for STEMI. Published reports were scanned by formal searches of electronic databases (MEDLINE and CENTRAL). All completed randomized trials of DES for STEMI were examined. No language restrictions were enforced. Individual patients' data were obtained from 11 of 13 trials, including a total of 972 patients with diabetes (616 [63.4%] randomized to DES and 356 [36.6%] to BMS). At long-term follow-up (median 1,095 days, interquartile range 1,087 to 1,460), DES significantly reduced the occurrence of target vessel revascularization (hazard ratio 0.42, 95% confidence interval 0.29 to 0.59, p <0.0001), without any significant difference in terms of mortality, late reinfarction, and ST (>1 year) with DES. In conclusion, this meta-analysis, based on individual patients' data from 11 randomized trials, showed that among patients with diabetes with STEMIs who undergo primary percutaneous coronary intervention, sirolimus-eluting stents and paclitaxel-eluting stents, compared with BMS, are associated with a significant reduction in target vessel revascularization at long-term follow-up, without any apparent concern in terms of mortality, despite the trend toward higher rates of reinfarction and ST.

Long-term outcome of second-generation everolimus-eluting stents and Endeavor zotarolimus-eluting stents in a prospective registry of ST-elevation myocardial infarction patients.

AIMS: The optimal drug-eluting stent (DES) in ST-elevation myocardial infarction (STEMI) patients remains unclear. We sought to compare the long-term performance of everolimus-eluting stents (EES) and Endeavor zotarolimus-eluting stents (E-ZES) in STEMI. METHODS AND RESULTS: The current analysis of a prospective registry included consecutive patients treated with EES or E-ZES for STEMI. Adjustment for measured confounders was done using Cox regression. In total, 931 patients met the inclusion criteria (412 EES and 519 E-ZES). Baseline characteristics were balanced, apart from a lower rate of renal insufficiency in EES. Median follow-up duration was 2.4 years (IQR 1.6-3.1). Mortality outcomes were similar. Up to three-year follow-up, the composite endpoint of cardiac death, target vessel-related myocardial infarction and target lesion revascularisation (TLR) was lower in EES; 9.7% vs. 13.7% in E-ZES (HR 0.64, 95% CI: 0.42-0.99), primarily driven by reduced TLR rates; 3.4% in EES vs. 7.3% in E-ZES (HR 0.46, 95% CI: 0.23-0.92). Definite stent thrombosis rates were low and similar between groups (1.1% in EES vs. 1.9% in E-ZES, p=0.190). CONCLUSIONS: Use of EES led to lower rates of the composite endpoint, driven by reduced TLR. This suggests that EES are more efficacious than Endeavor ZES in STEMI. Definite ST rates were low, and the strategy of second-generation DES implantation and the administration of upfront GP IIb/IIIa inhibitors appear to be safe in STEMI.

Impact of diabetes on long-term outcome after primary angioplasty: insights from the DESERT cooperation.

OBJECTIVE: Diabetes has been shown to be associated with worse survival and repeat target vessel revascularization (TVR) after primary angioplasty. The aim of the current study was to evaluate the impact of diabetes on long-term outcome in patients undergoing primary angioplasty treated with bare metal stents (BMS) and drug-eluting stents (DES). RESEARCH DESIGN AND METHODS: Our population is represented by 6,298 ST-segment elevation myocardial infarction (STEMI) patients undergoing primary angioplasty included in the DESERT database from 11 randomized trials comparing DES with BMS. RESULTS: Diabetes was observed in 972 patients (15.4%) who were older (P < 0.001), more likely to be female (P < 0.001), with higher prevalence of hypertension (P < 0.001), hypercholesterolemia (P < 0.001), and longer ischemia time (P < 0.001), and without any difference in angiographic and procedural characteristics. At long-term follow-up (1,201 ± 441 days), diabetes was associated with higher rates of death (19.1% vs. 7.4%; P < 0.0001), reinfarction (10.4% vs. 7.5%; P < 0.001), stent thrombosis (7.6% vs. 4.8%; P = 0.002) with similar temporal distribution--acute, subacute, late, and very late--between diabetic and control patients, and TVR (18.6% vs. 15.1%; P = 0.006). These results were confirmed in patients receiving BMS or DES, except for TVR, there being no difference observed between diabetic and nondiabetic patients treated with DES. The impact of diabetes on outcome was confirmed after correction for baseline confounding factors (mortality, P < 0.001; repeat myocardial infarction, P = 0.006; stent thrombosis, P = 0.007; TVR, P = 0.027). CONCLUSIONS: This study shows that among STEMI patients undergoing primary angioplasty, diabetes is associated with worse long-term mortality, reinfarction, and stent thrombosis in patients receiving DES and BMS. DES implantation, however, does mitigate the known deleterious effect of diabetes on TVR after BMS.

Value of platelet pharmacogenetics in common clinical practice of patients with ST-segment elevation myocardial infarction.

BACKGROUND: Antiplatelet drug resistance is a well-known problem, causing recurrent cardiovascular events. Multiple genetic polymorphisms have been related to antiplatelet resistance by several large trials, however data from common clinical practice is limited. We examined the influence of previously described polymorphisms, related to aspirin and clopidogrel resistance, on treatment outcome in a real life unselected population of patients presenting with ST-segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention. METHODS AND RESULTS: This cohort study consisted of 1327 patients with STEMI. Patients were treated according to a standardized guideline-based protocol. Nine polymorphisms, COX1 (-842A>G), P2Y1 (893C>T), GPIa (807C>T), GPIIIa (PlA1/A2), CYP2C19 (*2, *3 and *17), ABCB1 (3435T>C) and PON1 (576A>G), were genotyped. During 1 year of follow up the primary endpoint, a composite of cardiac death or recurrent myocardial infarction, was reached in 86 patients. The COX1 and CYP2C19*2 polymorphisms were associated with the primary endpoint, HR 2.55 (95% CI 1.48-4.40), P=0.001 and HR 2.03 (1.34-3.09) P=0.001, respectively. The combined analysis demonstrated a 2.5-fold increased risk for individuals with ≥ 2 risk alleles, P=6.9 × 10(-9). The association of COX1 was driven by mortality related events whereas that of CYP2C19*2 was mainly attributed to myocardial infarction and stent thrombosis. CONCLUSION: In this unselected, real life population of STEMI patient on dual-antiplatelet therapy, the polymorphisms COX1 -842A>G and CYP2C19*2 were determinants of thrombotic complications during follow-up. We show that in a clinical setting, testing for these polymorphisms could be of value in the identification of STEMI patients at risk for recurrent cardiovascular events.

Influence of gender on ischemic times and outcomes after ST-elevation myocardial infarction.

Previous studies investigating the influence of gender on ST-segment elevation myocardial infarction have reported conflicting results. The aim of this study was to assess the influence of gender on ischemic times and outcomes after ST-segment elevation myocardial infarction in patients treated with primary percutaneous coronary intervention in modern practice. The present multicenter registry included consecutive patients with ST-segment elevation myocardial infarctions treated with primary percutaneous coronary intervention at 3 hospitals. Adjusted mortality rates were calculated using Cox proportional-hazards analyses. In total, 3,483 patients were included, of whom 868 were women (25%). Women were older, had a higher risk factor burden, and more frequently had histories of malignancy. Men more often had cardiac histories and peripheral vascular disease. Ischemic times were longer in women (median 192 minutes [interquartile range 141 to 286] vs 175 minutes [interquartile range 128 to 279] in men, p = 0.002). However, multivariate linear regression showed that this was due to age and co-morbidity. All-cause mortality was higher at 7 days (6.0% in women vs 3.0% in men, p <0.001) and at 1 year (9.9% in women vs 6.6% in men, p = 0.001). After adjustment, female gender predicted 7 day all-cause mortality (hazard ratio 1.61, 95% confidence interval 1.06 to 2.46) and cardiac mortality (hazard ratio 1.58, 95% confidence interval 1.03 to 2.42) but not 1-year mortality. Moreover, gender was an independent effect modifier for cardiogenic shock, leading to substantially worse outcomes in women. In conclusion, ischemic times remain longer in women because of age and co-morbidity. Female gender independently predicted early all-cause and cardiac mortality after primary percutaneous coronary intervention, and a strong interaction between gender and cardiogenic shock was observed.

Drug-eluting vs bare-metal stents in primary angioplasty: a pooled patient-level meta-analysis of randomized trials.

BACKGROUND: Concerns have emerged regarding a higher risk of stent thrombosis after drug-eluting stent (DES) implantation, especially in the setting of ST-segment elevation myocardial infarction (STEMI). Our objective was to perform a meta-analysis using individual patient data to evaluate the long-term safety and effectiveness of DES compared with bare-metal stents (BMS) in patients undergoing primary percutaneous coronary intervention for STEMI. DATA SOURCES: Formal searches of electronic databases (MEDLINE and CENTRAL) and scientific session presentations from January 2000 to June 2011. STUDY SELECTION: We examined all completed randomized trials of DES for STEMI. DATA EXTRACTION: Individual patient data. DATA SYNTHESIS: Individual patient data were obtained from 11 of 13 trials identified, including a total of 6298 patients (3980 [63.2%] randomized to DES [99% sirolimus-eluting or paclitaxel-eluting stents] and 2318 [36.8%] randomized to BMS). At long-term follow-up (mean [SD], 1201 [440] days), DES implantation significantly reduced the occurrence of target-vessel revascularization (12.7% vs 20.1%; hazard ratio [95% CI], 0.57 [0.50-0.66]; P < .001, P value for heterogeneity, .20), without any significant difference in terms of mortality, reinfarction, and stent thrombosis. However, DES implantation was associated with an increased risk of very late stent thrombosis and reinfarction. CONCLUSIONS: The present pooled patient-level meta-analysis demonstrates that among patients with STEMI undergoing primary percutaneous coronary intervention, sirolimus-eluting and paclitaxel-eluting stents compared with BMS are associated with a significant reduction in target-vessel revascularization at long-term follow-up. Although there were no differences in cumulative mortality, reinfarction, or stent thrombosis, the incidence of very late reinfarction and stent thrombosis was increased with these DES.

Multimodality imaging in interventional cardiology.

'Multimodality' imaging--the side-by-side interpretation of data obtained from various noninvasive imaging techniques, such as echocardiography, radionuclide techniques, multidetector CT (MDCT), and MRI--allows anatomical, morphological, and functional data to be combined, increases diagnostic accuracy, and improves the efficacy of cardiovascular interventions and clinical outcomes. During the past decade, advances in software and hardware have allowed co-registration of various imaging modalities, resulting in cardiac 'hybrid' or 'fusion' imaging. In this Review, we discuss the roles of both multimodality and hybrid imaging in three broad areas of cardiology--coronary artery disease (CAD), heart failure, and valvular heart disease. In the evaluation of CAD, integration of either single-photon emission computed tomography (SPECT) or PET with CT coronary angiography provides both morphological and functional data in a single procedure. Accordingly, the functional consequences (myocardial hypoperfusion on SPECT or PET) of anatomical pathology (coronary anatomy on MDCT or MRI) can be assessed. Co-registration of PET and MRI data sets to provide cellular and molecular information on plaque composition and stability is now possible. Furthermore, novel imaging modalities have been implemented to guide electrophysiological and transcatheter-based procedures, such as cardiac resynchronization therapy (an established treatment for patients with heart failure), and transcatheter valve repair or replacement procedures.

Five-year clinical follow-up from the MISSION! Intervention Study: sirolimus-eluting stent versus bare metal stent implantation in patients with ST-segment elevation myocardial infarction, a randomised controlled trial.

AIMS: To evaluate the clinical outcomes of sirolimus-eluting stent (SES) versus bare metal stent (BMS) implantation in patients with ST-segment elevation myocardial infarction (STEMI) at long-term follow-up. METHODS AND RESULTS: After five years, 310 STEMI patients randomly assigned to implantation of either SES or BMS, were compared. Survival rates were comparable between groups (SES 94.3% vs. BMS 92.8%, p=0.57), as were the rates of reinfarction (10.6% vs. 13.7%, p=0.40), freedom of death/re-MI (84.4% vs. 79.8%, p=0.29) and target vessel failure (14.9% vs. 21.7%, p=0.11). Likewise, rates of overall stent thrombosis (ST) (5.4% vs. 2.7%, p=0.28) and very late ST (4.1% vs. 0.7%, p=0.07) did not significantly differ between the SES- and BMS-group. In 184 patients with IVUS data, definite and definite/probable VLST was more common in those with late stent malapposition versus those without late stent malapposition (4.3% and 6.6% vs. no events [p=0.018 and p=0.004], respectively). The cumulative incidences of target vessel and target lesion revascularisation (TVR and TLR) were not significantly lower in the SES-group (11.2% vs. 17.9%, p=0.09 and 7.2% vs. 12.9%, p=0.08), as was the rate of clinically driven TLR (6.6% vs. 9.5%, p=0.30). CONCLUSIONS: SES implantation was neither associated with increased rates of major adverse cardiac events, nor with a reduction in re-intervention, compared to implantation of a BMS in patients with STEMI after five years. However, a trend of more very late stent thrombosis was observed after SES implantation (ISRCTN62825862).