Sex- and age-related differences in clinical outcome after primary percutaneous coronary intervention.

AIMS: To compare the outcome after primary percutaneous coronary intervention (PPCI) according to sex and age, including comparison of sex- and age-specific mortality of PPCI patients with that of the general population. METHODS AND RESULTS: This population-based follow-up study included 7,385 STEMI patients treated with PPCI and 42,965 matched general population controls. The primary outcome was the composite endpoint of mortality, reinfarction, and stroke at 30 days, one year, and two years. Women were older and had a more adverse baseline risk profile than men. The risks of the composite endpoint after 30 days, one year, and two years were 9.1%, 16.0%, and 20.0%, respectively, for women compared to 5.8%, 10.6%, and 14.0% for men (adjusted hazard ratio [HR] [30 days]=1.16 [0.95-1.41], adjusted HR [one year]=1.18 [1.02-1.37], and adjusted HR [two years]=1.14 [0.99-1.30]). The risk of an adverse outcome increased similarly among women and men with increasing age. When comparing patients and controls, we found a higher mortality among patients up to 90 days after PPCI. However, after 90 days, the mortality among the PPCI patients was comparable to the mortality in the general population in all sex and age groups. CONCLUSIONS: Clinical outcome after PPCI was comparable in men and women after controlling for possible confounding. After 90 days post-PPCI, the mortality of treated patients was comparable to the mortality of the general population, independent of sex and age.

Global left ventricular longitudinal systolic strain for early risk assessment in patients with acute myocardial infarction treated with primary percutaneous intervention.

BACKGROUND: Left ventricular systolic function is a key determinant of outcome after ST-segment elevation myocardial infarction (STEMI). The aim of this study was to study speckle-tracking global longitudinal strain (GLS) for early risk evaluation in STEMI and compare it with left ventricular ejection fraction (LVEF), wall motion score index (WMSI), and end-systolic volume index (ESVI). METHODS: Five-hundred seventy-six patients underwent echocardiography ≤24 hours after primary percutaneous coronary intervention for STEMI. The end point was the composite of death, hospitalization with reinfarction, congestive heart failure, or stroke. Associations with outcome were assessed by multivariate Cox regression with adjustment for clinical parameters. Hazard ratios (HRs) for events within the first year are reported per absolute percentage GLS increase. RESULTS: During a median follow-up period of 24 months, 162 patients experienced at least one event. GLS was associated with the composite end point (adjusted HR, 1.20; 95% confidence interval [CI], 1.12-1.29) and also when controlling for LVEF (adjusted HR, 1.17; 95% CI, 1.07-1.29) and ESVI (adjusted HR, 1.18; 95% CI, 1.08-1.28). Although WMSI was significantly associated with outcome beyond any association accounted for by GLS, a borderline significant association was found after controlling for WMSI (adjusted HR for GLS, 1.10; 95% CI, 1.00-1.21). When GLS or WMSI was known, there was no significant association between LVEF or ESVI and outcome. CONCLUSIONS: In a large population of patients with STEMI, GLS and WMSI were comparable and both superior for early risk assessment compared with volume-based left ventricular function indicators such as LVEF and ESVI. Compared with WMSI, the advantage of GLS is the provision of a semiautomated quantitative measure.

Microarray expression analysis in delayed cardioprotection: the effect of exercise, AICAR, or metformin and the possible role of AMP-activated protein kinase (AMPK).

AMP-activated protein kinase (AMPK) is an enzyme which may be involved in cardioprotective mechanisms in the ischemic heart. Exercise, AICAR, and metformin, all known activators of AMPK, induce delayed cardioprotection which protects the heart against ischemia-reperfusion injury. The objective was to determine the effect of exercise, AICAR, and metformin on gene expression profile and to demonstrate possible interactions in different genes and functions. Rats were divided into either an exercise, AICAR, metformin, or control group. 3, 12, and 24 h after either a single bout of exercise training, a single injection of AICAR or a single dose of metformin, hearts were removed and gene expression profiles were analyzed in tissue from the left ventricle using Affymetrix gene chip probe arrays. Ingenuity Pathway Analysis (IPA) tool was used to analyze the regulated genes for relevant functions and diseases. Each gene chip identified up to 30,000 different probesets of which Ingenuity identified approximately up to 12,000 genes. A total of 147, 304, and 114 different genes in the left ventricle whose expressions were altered >2.0-fold were identified in the exercise, AICAR, and metformin group, respectively. Seventy eight different genes were overlapping the exercise and AICAR group at 24 h. Ingenuity identified six overlapping genes between the exercise, AICAR, and metformin groups including NR4A3, TNFRSF12A, HBB, PENK, PAP, and MAP4K4. IPA software revealed an overabundance of focus molecules in all three intervention groups involving functions related to cell death, cellular growth and proliferation, gene expression and cancer. Exercise, AICAR, and metformin regulate several genes in the rat myocardium with the majority of overlapping genes observed in the exercise and AICAR group. Changes in gene programming mainly involved inflammatory and opioid systems recognized as cardioprotective pathways. Some of these genes may represent possible candidate genes involved in the molecular mechanisms of AMPK-induced delayed PC.

Nonsteroidal antiinflammatory drug use and cardiovascular risks after coronary stent implantation.

STUDY OBJECTIVE: To determine whether use of nonselective nonsteroidal antiinflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2)-selective inhibitors in patients with coronary stents increased the 3-year rate of major adverse cardiovascular events (MACE). DESIGN: Population-based cohort study. DATA SOURCES: The Danish National Patient Registry, the Western Denmark Heart Registry, the Danish Nationwide Prescription Database, the Danish Civil Registration System, and the National Registry of Causes of Deaths. PATIENTS: A total of 13,001 patients who underwent first-ever percutaneous coronary intervention with stent implantation between January 1, 2002, and June 30, 2005. MEASUREMENTS AND MAIN RESULTS: All patients were followed for 3 years after stent implantation for MACE, defined as the first occurrence of myocardial infarction, stent thrombosis, target-lesion revascularization, or cardiac death. Patients' comorbidities were identified from the hospital registries; time-varying use of NSAIDs and concomitant drugs was determined from the Danish Nationwide Prescription Database. For each clinical outcome (MACE), the 3-year risk was computed. We used Cox proportional-hazards regression analysis to compute hazard ratios (HRs) as a measure of relative risk, controlling for potential confounders. During the follow-up period, 5407 patients (41.6%) redeemed at least one NSAID prescription. There were 686 hospitalizations for myocardial infarction (5.3% of patients), 146 for stent thrombosis (1.1%), and 1091 for target-lesion revascularization (8.4%). A total of 1220 patients (9.4%) died during the follow-up period; 637 (4.9%) died of cardiac causes. Compared with no NSAID use, the adjusted HR for MACE was 1.04 (95% confidence interval [CI] 0.83-1.31) for nonselective NSAID use and 1.00 (95% CI 0.81-1.25) for COX-2 inhibitor use. CONCLUSION: Use of nonselective NSAIDs or COX-2 inhibitors was not associated with an increased rate of MACE in patients with coronary stents. However, we cannot rule out small risks associated with individual NSAIDs.

Remote ischemic per-conditioning: a novel therapy for acute stroke?

BACKGROUND AND PURPOSE: Remote ischemic preconditioning is a phenomenon by which a short period of sublethal ischemia to an organ protects against subsequent ischemia in another organ. We have recently demonstrated that remote ischemic conditioning by transient hind limb ischemia delivered during ischemia and before reperfusion can provide potent cardioprotection, a phenomenon we termed per-conditioning. This study evaluated whether remote ischemic per-conditioning may provide neuroprotection in a clinically relevant rat model of acute ischemic stroke. METHODS: Remote ischemic conditioning by transient limb ischemia was used in a rat transient middle cerebral artery occlusion model of acute stroke. A total of 39 P60 rats were randomly allocated to receive preconditioning, per-conditioning, or sham conditioning. Cerebral ischemia was maintained for 120 minutes followed by reperfusion. The resulting infarct size at 24 hours was quantified using computerized image analysis of 2-3-5-triphenyl tetrazolium chloride-stained brain sections. RESULTS: Compared with control, both pre- and per-conditioning significantly reduced brain infarct size with the more clinically relevant per-conditioning stimulus being superior to preconditioning. CONCLUSIONS: Remote per-conditioning by transient limb ischemia is a facile, clinically relevant stimulus that provides potent neuroprotection in a model of regional brain ischemia-reperfusion injury. Further studies are required to better understand the mechanisms and biology of this response before translation to randomized controlled trials of remote per-conditioning for acute ischemic stroke.

System delay and timing of intervention in acute myocardial infarction (from the Danish Acute Myocardial Infarction-2 [DANAMI-2] trial).

The interval from the first alert of the healthcare system to the initiation of reperfusion therapy (system delay) is associated with mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention (pPCI). The importance of system delay in patients treated with fibrinolysis versus pPCI has not been assessed. We obtained data on system delay from the Danish Acute Myocardial Infarction-2 study, which randomized 1,572 patients to fibrinolysis or pPCI. The study end points were 30-day and 8-year mortality. The short system delays were associated with reduced absolute mortality in both the fibrinolysis group (<1 hour, 5.6%; 1 to 2 hours, 6.9%; 2 to 3 hours, 9.5%; and >3 hours, 11.5%; test for trend, p = 0.08) and pPCI group (<1 hour, not assessed; 1 to 2 hours, 2.6%; 2 to 3 hours, 7.5%; >3 hours, 7.7%; test for trend, p = 0.02). The lowest 30-day mortality was obtained with pPCI and a system delay of 1 to 2 hours (vs fibrinolysis within <1 hour, adjusted hazard ratio 0.33; 95% confidence interval 0.10 to 1.10; p = 0.07; vs fibrinolysis within 1 to 2 hours, adjusted hazard ratio 0.37; 95% confidence interval 0.14 to 0.95; p = 0.04). pPCI and system delay >3 hours was associated with a similar 30-day and 8-year mortality as fibrinolysis within 1 to 2 hours. In conclusion, short system delays are associated with reduced mortality in patients with ST-segment elevation myocardial infarction treated with fibrinolysis as well as pPCI. pPCI performed with a system delay of <2 hours is associated with lower mortality than fibrinolysis performed with a faster or similar system delay.

Comparison of primary percutaneous coronary intervention in real-world populations versus clinical trial populations.

The efficacy of primary percutaneous coronary intervention (PPCI) has been documented in several randomized-controlled trials. We sought to examine the clinical outcome after PPCI of real-world patients eligible and ineligible for inclusion in a randomized trial (DANAMI-2) and to compare it to the outcome of the DANAMI-2 population. We did a population-based follow-up study comparing 1,320 consecutive real-world patients treated with PPCI from 2004 to 2006 to 686 patients treated with PPCI in the DANAMI-2 trial. By reviewing medical records we determined whether the real-world patients were eligible in the DANAMI-2 trial. The real-world population had a more adverse baseline risk profile. Cumulative incidences of the composite end point of all-cause mortality, reinfarction, and stroke after 1 year and 2 years were 17.8% and 22.0%, respectively, in the real-world population compared to 13.6% and 17.3% in the DANAMI-2 population. After adjustment for differences in baseline characteristics and treatment, differences persisted after 1 year (adjusted hazard ratio 1.8, 95% confidence interval 1.3 to 2.6) and 2 years (adjusted hazard ratio 1.7, 95% confidence interval 1.2 to 2.3). Results for the real-world patients eligible according to DANAMI-2 criteria were comparable to the results from the DANAMI-2 trial. In conclusion, real-world patients had a more adverse baseline prognostic profile and a poorer clinical outcome compared to the DANAMI-2 patients. However, clinical outcome in the real-world patients eligible in the DANAMI-2 trial was comparable to that for the DANAMI-2 patients after invasive and medical treatment.

Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial.

BACKGROUND: Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty. We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infarction, and done before primary percutaneous coronary intervention, increases myocardial salvage. METHODS: 333 consecutive adult patients with a suspected first acute myocardial infarction were randomly assigned in a 1:1 ratio by computerised block randomisation to receive primary percutaneous coronary intervention with (n=166 patients) versus without (n=167) remote conditioning (intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff). Allocation was concealed with opaque sealed envelopes. Patients received remote conditioning during transport to hospital, and primary percutaneous coronary intervention in hospital. The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention, measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment; analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00435266. FINDINGS: 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria, 32 were lost to follow-up, and 77 did not complete the follow-up with data for salvage index. Median salvage index was 0.75 (IQR 0.50-0.93, n=73) in the remote conditioning group versus 0.55 (0.35-0.88, n=69) in the control group, with median difference of 0.10 (95% CI 0.01-0.22; p=0.0333); mean salvage index was 0.69 (SD 0.27) versus 0.57 (0.26), with mean difference of 0.12 (95% CI 0.01-0.21; p=0.0333). Major adverse coronary events were death (n=3 per group), reinfarction (n=1 per group), and heart failure (n=3 per group). INTERPRETATION: Remote ischaemic conditioning before hospital admission increases myocardial salvage, and has a favourable safety profile. Our findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes. FUNDING: Fondation Leducq.

Primary angioplasty versus fibrinolysis in acute myocardial infarction: long-term follow-up in the Danish acute myocardial infarction 2 trial.

BACKGROUND: The Danish Acute Myocardial Infarction 2 (DANAMI-2) study found that primary angioplasty (primary percutaneous coronary intervention [pPCI]) compared with fibrinolysis reduced 30-day adverse events in patients with ST-segment elevation myocardial infarction. The present study investigated whether the benefit of pPCI was maintained at a long-term follow-up. METHODS AND RESULTS: We randomly assigned 1572 patients with ST-segment elevation myocardial infarction-1129 patients at referral hospitals and 443 patients at invasive hospitals-to pPCI or fibrinolysis. Median time from randomization to arrival in the catheterization laboratory for patients admitted to referral hospitals was 67 minutes, with 96% of patients arriving in the catheterization laboratory within 120 minutes. The primary study end point was a composite of death or reinfarction. Median follow-up time was 7.8 years. For the primary end point, 8-year cumulative incidence (1-Kaplan-Meier) was 34.8% in the pPCI group and 41.3% in the fibrinolysis group (hazard ratio, 0.78; 95% confidence interval, 0.66 to 0.92). Reinfarction rates were reduced in the pPCI group (11.7% versus 18.5%; hazard ratio, 0.60; 95% confidence interval, 0.46 to 0.77). Among patients randomized at referral hospitals, pPCI reduced reinfarction (13% versus 18.5%; hazard ratio, 0.66; 95% confidence interval, 0.49 to 0.89) and mortality (26.7% versus 33.3%; hazard ratio, 0.78; 95% confidence interval, 0.63 to 0.97). CONCLUSIONS: The benefit of pPCI over fibrinolysis was maintained at a long-term follow-up. pPCI reduced the risk of reinfarction in the overall cohort and reduced reinfarction and mortality among patients randomized at referral hospitals. This result reinforces that pPCI should be offered to ST-segment elevation myocardial infarction patients when interhospital transport to an invasive hospital can be completed within 120 minutes.

Evaluation of the relationship between hyperinsulinaemia and myocardial ischaemia/reperfusion injury in a rat model of depression.

Major depression is associated with medical co-morbidity, such as ischaemic heart disease and diabetes, but the underlying pathophysiological mechanisms remain unclear. The FSL (Flinders Sensitive Line) rat is a genetic animal model of depression exhibiting features similar to those of depressed individuals. The aim of the present study was to compare the myocardial responsiveness to I/R (ischaemia/reperfusion) injury and the effects of IPC (ischaemic preconditioning) in hearts from FSL rats using SD (Sprague-Dawley) rats as controls and to characterize differences in glucose metabolism and insulin sensitivity between FSL and SD rats. Hearts were perfused in a Langendorff model and were subjected or not to IPC before 40 min of global ischaemia, followed by 120 min of reperfusion. Myocardial infarct size was found to be significantly larger in the FSL rats than in the SD rats following I/R injury (62.4+/-4.2 compared with 46.9+/-2.9%; P<0.05). IPC reduced the infarct size (P<0.01) and improved haemodynamic function (P<0.01) in both FSL and SD rats. No significant difference was found in blood glucose levels between the two groups measured after 12 h of fasting, but fasting plasma insulin (70.1+/-8.9 compared with 40.9+/-4.7 pmol/l; P<0.05) and the HOMA (homoeostatic model assessment) index (P<0.01) were significantly higher in FSL rats compared with SD rats. In conclusion, FSL rats had larger infarct sizes following I/R injury and were found to be hyperinsulinaemic compared with SD rats, but appeared to have a maintained cardioprotective mechanism against I/R injury, as IPC reduced infarct size in these rats. This animal model may be useful in future studies when examining the mechanisms that contribute to the cardiovascular complications associated with depression.

Timing, causes, and predictors of death after three years' follow-up in the Danish Multicenter Randomized Study of Fibrinolysis versus Primary Angioplasty in Acute Myocardial Infarction (DANAMI-2) trial.

This study evaluated the timing, causes, and predictors of death during long-term follow-up after primary angioplasty with stent implantation versus in-hospital fibrinolysis with a tissue plasminogen activator (alteplase). We randomized 1,572 patients with ST-elevation myocardial infarction to primary angioplasty or alteplase and followed them for 3 years. The causes of death were prospectively assessed by an end point committee unaware of the study treatment. A total of 225 patients (14.3%) died, 113 within the first 30 days and 112 between 31 days and 3 years. The mortality and causes of death did not differ between the 2 treatments. The causes of death were cardiogenic shock/congestive heart failure (41%), sudden death (17%), other cardiac death (10%), cancer (12%), and other noncardiac death (20%). Cardiac death was predominant during the first month only (86% of early deaths), and noncardiac death and cardiac death were equally frequent after 30 days (49% and 51% of late deaths, respectively). Independent predictors of death after discharge were age, left ventricular ejection fraction, diabetes, Killip class, and a lack of treatment with a beta blocker or statin. In conclusion, the causes of death did not differ between alteplase treatment and primary angioplasty with stent implantation. One half of the deaths within 3 years after ST-elevation myocardial infarction occurred during the first 30 days, and cardiac death was predominant during the first 30 days only.

Blockage of receptor for advanced glycation end products prevents development of cardiac dysfunction in db/db type 2 diabetic mice.

AIMS: Activation of the receptor for advanced glycation end products (RAGE) is associated with long-term complications in diabetes mellitus. In this study, we tested whether RAGE activation in the diabetic myocardium is implicated in the development of cardiac dysfunction. METHODS AND RESULTS: Using MRI and conductance catheter techniques, we evaluated cardiac function in a type 2 diabetic mouse model (db/db), and assessed the effect of blocking RAGE with a RAGE antibody. Gene expressions were evaluated in samples of myocardial tissue. Diabetic db/db mice demonstrated an accelerated age-dependent deterioration in cardiac function associated with altered expression of genes related to cardiac structure and function. Blockage of RAGE signalling prevented the reduction in systolic function (preload recruitable stroke work: 109.8 +/- 13.8 vs. 94.5 +/- 14.9 mmHg/microL, P = 0.04) and development of increased LV diastolic chamber stiffness (0.18 +/- 0.05 vs. 0.27 +/- 0.07 mmHg, P = 0.01). The cardiac expression of collagen (col1a1) was reduced by approximately 45% and the expression of myosin was switched from the foetal isoform (MHCbeta) to the adult isoform (MHCalpha). CONCLUSION: Activation of RAGE is a significant pathogenetic mechanism for the development of cardiac dysfunction in type 2 diabetes. The underlying mechanisms involve not only the passive biophysical properties of the myocardium but also myocyte function.

Antithrombotic therapy and outcomes of patients with atrial fibrillation following primary percutaneous coronary intervention: results from the APEX-AMI trial.

AIMS: To assess the incidence and timing of atrial fibrillation (AF), describe antithrombotic therapy use, and evaluate the association of AF with 90 day mortality and other secondary clinical outcomes. METHODS AND RESULTS: We studied 5745 ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention (PCI) in APEX-AMI. Approximately 11% had AF during hospitalization. Atrial fibrillation prevalence at baseline and at discharge was 4.8% [confidence interval (CI) 4.3-5.4%] and 2.5% (CI 2.1-2.9%), respectively. The proportion of 5466 patients without AF at baseline who developed new onset AF was 6.3% (CI 5.6-6.9%). This corresponded to 9.3 cases of new onset AF/1000 patient days at risk. New onset AF was independently associated with 90 day mortality [adjusted hazard ratio (HR) 1.81; 95% CI 1.06-3.09; P = 0.029] after accounting for baseline covariates and in-hospital procedures and complications. New onset AF was associated with shock (adjusted HR 3.81; 95% CI 1.88-7.70; P = 0.0002), congestive heart failure (adjusted HR 2.66; 95% CI 1.74-4.06; P < 0.0001), and stroke (adjusted HR 2.98; 95% CI 1.47-6.04; P = 0.0024) in models accounting for baseline covariates. Of AF patients, 55% did not receive oral anticoagulation therapy at discharge. Among patients with coronary stents, 5.1% were discharged on triple therapy. Patients at highest risk of stroke (CHADS(2) score > or =2) were least likely to receive oral anticoagulation at discharge (39%). Warfarin use in patients with AF at discharge (43.4%) was associated with lower rates of 90 day mortality and stroke. CONCLUSION: Atrial fibrillation prevalence at baseline and at discharge was 4.8 and 2.5%, respectively. The proportion of patients who developed new onset AF was 6.3%. New onset AF was independently associated with 90 day mortality and was a marker of adverse outcomes in patients undergoing primary PCI.

5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases myocardial glucose uptake during reperfusion and induces late pre-conditioning: potential role of AMP-activated protein kinase.

Late pre-conditioning protects against myocardial ischaemic-reperfusion injury. AMP-activated protein kinase (AMPK) is activated by exercise and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Early pre-conditioning involves AMPK activation and increased myocardial glucose uptake. The aim of the present study was to determine whether AICAR activates myocardial AMPK and induces late pre-conditioning and whether myocardial glucose uptake during reperfusion was modulated. Twenty-four hours after AICAR treatment or exercise, Wistar rats were subjected to ischaemia and reperfusion in a Langendorff model and compared to control rats. AMPK activity increased immediately 2.5-fold in AICAR-treated animals (P < 0.01) and twofold in exercised animals (P < 0.05). AICAR and exercise reduced infarct size by 60% and 50% (both P < 0.01), respectively, and increased myocardial glucose uptake during reperfusion (AICAR; 45%, P < 0.05, exercise; 40%, P < 0.05). In conclusion, AICAR induces late pre-conditioning and increases myocardial glucose uptake during reperfusion in rat hearts. AICAR and exercise activate AMPK, suggesting a role of AMPK in the signalling mechanisms behind late pre-conditioning.

Infarct size and myocardial salvage after primary angioplasty in patients presenting with symptoms for <12 h vs. 12-72 h.

AIMS: Primary angioplasty for ST-segment elevation myocardial infarction (STEMI) is recommended only if symptom duration is <12 h. We evaluated final infarct size (FIS) and myocardial salvage in early presenters (<12 h) vs. late presenters (12-72 h) undergoing primary angioplasty. METHODS AND RESULTS: Myocardial perfusion imaging (MPI) was performed acutely to assess area at risk (AAR) before angioplasty and repeated after 30 days to assess FIS (% of LV myocardium), salvage index (% non-infarcted AAR), and left ventricular ejection fraction (LVEF). Late presenters (n = 55) compared with early presenters (n = 341) had larger median FIS [14% (inter-quartile range 3-30) vs. 7% (2-18), P = 0.005], lower salvage index [53% (27-89) vs. 69% (45-91), P = 0.05], and lower LVEF [48% (44-58%) vs. 53% (47-59), P = 0.04]. However, FIS, salvage index, and LVEF correlated weakly with symptom duration (R(2)-values <0.10). In patients with TIMI-flow 0 (n = 247), late presenters had lower salvage index than early presenters [44% (23-73) vs. 57% (42-86), P = 0.03], but substantial salvage (>50% of AAR) was observed in 41% of late presenters despite total infarct-artery occlusion. CONCLUSION: FIS is larger in late presenters (>12 h) than early presenters after primary angioplasty for STEMI. However, substantial myocardial salvage can be obtained beyond the 12 h limit, even when the infarct-related artery is totally occluded.

Clinical reinfarction according to infarct location and reperfusion modality in patients with ST elevation myocardial infarction. A DANAMI-2 long-term follow-up substudy.

OBJECTIVES: To evaluate clinical reinfarction during a 3-year follow-up after randomization to primary angioplasty versus fibrinolysis in anterior and non-anterior ST elevation myocardial infarction (STEMI). METHODS: Clinical reinfarction was prospectively assessed by an endpoint committee blinded to the study treatment. RESULTS: At 30 days, primary angioplasty compared with fibrinolysis reduced the reinfarction rate both in anterior STEMI patients (n = 823; 2.5 vs. 5.6%, p = 0.02) and in non-anterior STEMI patients (n = 743; 0.8 vs. 7.4%, p < 0.001). After 3 years, the reduction in reinfarction rate was no longer present in anterior STEMI patients (11.2 vs. 11.2%, p = 0.86), but persisted in non-anterior STEMI patients (5.2 vs. 13.5%, p < 0.001). Reinfarction after anterior STEMI carried a higher mortality than reinfarction after non-anterior STEMI (37.6 vs. 15.3%, p = 0.01). Independent predictors of death were: age [hazard ratio (HR) per 1-year increase in age = 1.08 (1.07-1.09)], clinical reinfarction [HR = 5.15 (3.57-7.43)], anterior index STEMI [HR = 1.65 (1.24-2.19)], and Killip class > or =2 [HR = 1.42 (1.01-2.00)]. The additional late reinfarctions after angioplasty for anterior STEMI were located within the angioplasty-treated target segment. Anterior STEMI patients had smaller mean target vessel diameter, which was associated with reinfarction. CONCLUSIONS: Clinical reinfarction is an independent predictor of death. The early superiority of primary angioplasty over fibrinolysis on reinfarction rate after anterior STEMI diminished during long-term follow-up.

Temporal course of pregnancy-associated plasma protein-A in angioplasty-treated ST-elevation myocardial infarction patients and potential significance of concomitant heparin administration.

Pregnancy-associated plasma protein-A (PAPP-A) is a putative plaque instability marker. In acute coronary syndromes, the disrupted culprit plaque contains abundant PAPP-A, and circulating PAPP-A levels predict clinical outcomes. Determinants of circulating PAPP-A levels, however, are not fully understood, and the potential role of concomitant heparin administration has not previously been evaluated. The purposes of the present study were to evaluate in-hospital levels of PAPP-A compared with other circulating biomarkers in patients with acute myocardial infarctions and to explore the potential impact of concomitant heparin administration on PAPP-A levels in an animal experiment. Group A comprised 84 patients with ST elevation myocardial infarctions (STEMIs) who were treated with heparin and transferred for primary percutaneous coronary intervention. Plasma samples were obtained at the time of primary percutaneous coronary intervention, twice within the next 24 hours, and subsequently daily during hospitalization. Levels of PAPP-A, troponin T, soluble cluster of differentiation 163, N-terminal-pro-brain natriuretic peptide, and high-sensitivity C-reactive protein were determined. PAPP-A levels were also determined in 2 historical cohorts not given heparin: 14 patients with STEMIs (group B) and 56 patients with non-ST elevation myocardial infarctions (group C). The impact of concomitant heparin administration on the clearance of PAPP-A from the circulation was also explored in mice. In group A, PAPP-A levels were increased in the initial plasma sample in 95% of patients presenting within 3 hours of symptom onset, whereas increased levels of troponin T, soluble cluster of differentiation 163, N-terminal-pro-brain natriuretic peptide, and high-sensitivity C-reactive protein were detectable in 45%, 15%, 50%, and 35% of patients, respectively. Compared with group A, lower levels of PAPP-A were observed in the initial plasma samples drawn in groups B (p = 0.07) and C (p <0.001) not given heparin. In the animal experiment, concomitant heparin administration resulted in increased levels of PAPP-A and delayed clearance of PAPP-A from the circulation. In conclusion, PAPP-A is markedly elevated in the earliest hours after the onset of symptoms in patients with STEMIs treated with heparin and primary percutaneous coronary intervention, and in animal studies, heparin administration is associated with a significant increase in PAPP-A levels, presumably because of the detachment of PAPP-A from the vessel wall. If future studies confirm that concomitant heparin administration also increases PAPP-A levels in humans, the prognostic role of PAPP-A in patients with STEMIs needs to be reevaluated.

Is there any time left for primary percutaneous coronary intervention according to the 2007 updated American College of Cardiology/American Heart Association ST-segment elevation myocardial infarction guidelines and the D2B alliance?

Early reperfusion therapy is essential in the treatment of patients with ST-segment elevation myocardial infarction. Fibrinolytic therapy is a feasible reperfusion strategy to be initiated at any hospital and preferably in the pre-hospital phase. Primary percutaneous coronary intervention (PPCI) is acknowledged as a superior reperfusion strategy when initiated in a timely fashion. It is also the preferred reperfusion therapy in patients who exhibit cardiogenic shock and in patients with contraindications to fibrinolysis. However, in many regions, it is difficult to establish a successful PPCI strategy because it mandates optimal pre-hospital and in-hospital triage to ensure acceptable treatment delays. The 2007 updated American College of Cardiology/American Heart Association ST-Segment Elevation Myocardial Infarction Guidelines stress that "the focus for PPCI is from first medical contact because in regionalization strategies, extra time may be taken to transport patients to a center that performs the procedure" and that "time from Emergency Medical Services arrival to balloon inflation should be <90 minutes." When considering fibrinolysis, however, the guidelines accept a door-to-needle time of 30 min from arrival at the local hospital. Is there evidence to justify that, in the PPCI setting, the clock starts ticking upon the arrival of the Emergency Medical Services but, in the setting of in-hospital fibrinolysis, it does not start until a patient's arrival at the local hospital?

Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 hours after administration.

The UK Prospective Diabetes Study demonstrated that the hypoglycaemic drug metformin is associated with a reduction in cardiovascular events in a group of obese type 2 diabetes patients. The energy sensing enzyme AMP-activated protein kinase (AMPK) has been indicated to play an important protective role in the ischaemic heart and is activated by metformin. The aim of this study was to determine whether a single dose of metformin protects the myocardium against experimentally induced ischaemia 24 hr after the administration, and furthermore to determine whether a single dose of metformin results in an acute increase in myocardial AMPK activity. Wistar rats were given either a single oral dose of metformin (250 mg/kg body weight), or a single oral dose of saline. After 24 hr, the hearts were Langendorff-perfused and subjected to 45 min. of coronary artery occlusion. Infarct size was determined by staining with triphenyltetrazoliumchloride (TTC) and Evans Blue and expressed as a percentage of the risk zone (IS/AAR %). Isoform specific AMPK activity was measured 2 hr after administration of metformin or saline. Infarct size was significantly reduced in the metformin treated (I/R: 19.9 +/- 3.9%versus 36.7 +/- 3.6%, P < 0.01, n = 8-14) compared to the control group. A single oral dose of metformin resulted in an approximately ~2-fold increase in AMPK-alpha2 activity 2 hr after administration (P < 0.015, n = 10). In conclusion, a single dose of metformin results in an acute increase in myocardial AMPK activity measured 2 hr after administration and induces a significant reduction in myocardial infarct size 24 hr after metformin administration. Increased AMPK activity may be an important signal mediator involved in the mechanisms behind the cardioprotective effects afforded by metformin.

Cardioprotection by L-glutamate during postischaemic reperfusion: reduced infarct size and enhanced glycogen resynthesis in a rat insulin-free heart model.

1. Previously, we found that administration of high-dose L-glutamate during postischaemic reperfusion improves haemodynamic recovery and enhances glycogen resynthesis. In the present study, we investigated whether the same effect occurs in an insulin-free model and whether glutamate administration reduces infarct size. Further, we studied whether the cardioprotective effect of glutamate depends on preserved glutamate transamination and K(ATP) channel activity. 2. In a rat isolated, insulin-free, perfused heart model, we compared the effects of administration of L-glutamate (10 mmol/L) during either 45 min no-flow regional ischaemia plus 120 min reperfusion or reperfusion alone on infarct size and left ventricular (LV) recovery. The effect of glutamate on glycogen metabolism was studied in a model of 30 min global no-flow ischaemia and 60 min reperfusion. In both models, the effects of inhibition of glutamate transamination and K(ATP) channel activity were examined by adding amino-oxyacetate (an aminotransferase inhibitor; 0.1 mmol/L) and glibenclamide (a K(ATP) blocker; 10 mmol/L), respectively. 3. Administration of L-glutamate reduced infarct size by 60% (P < 0.01) and improved postischaemic LV function (developed pressure and rate pressure product; P < 0.05). L-Glutamate increased glycogen content after 60 min reperfusion by 65% (P < 0.01). Amino-oxyacetate, as well as glibenclamide, abolished the glutamate-mediated reduction in infarct size, haemodynamic improvement and glycogen resynthesis during reperfusion. 4. In conclusion, L-glutamate administration from the start of postischaemic reperfusion exerts cardioprotective effects, including reduced infarct size, improved haemodynamic recovery and enhanced glycogen resynthesis. These effects depend on preserved transamination of glutamate and K(ATP) channel activity, but not on insulin administration.