Introduction: Biomarker research related to protease-activated receptor-1 (PAR-1) inhibition with vorapaxar in humans has essentially focused on platelets. Follow-up (FU) time has been short, whereas in the current study, focus has been on endothelial function during both short- and long-term PAR-1 inhibition. Aim: To assess short- and long-term effects of vorapaxar (V) as compared to Placebo (PL) on the following biomarkers: Angiopoietin-2 (ANGPT2), Angiopoietin-like 4 (ANGPTL4), VEGF, ICAM-1, VCAM-1, E-Selectin (ESEL), von Willebrand Factor (VWF), Thrombomodulin (TM), PAI-1 and PAI-2. Methods: In an independent collective subproject performed in Norway, post-MI patients at steady state were recruited from the “Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients with Atherosclerosis” (TRA2ᵒP-TIMI 50) and NSTEMI patients were recruited from the “Thrombin Receptor Antagonist for Clinical Event Reduction in acute coronary syndrome” (TRACER) trial. Biomarkers were measured in duplicate by enzyme immunoassays (EIA) in citrated plasma at one month follow-up and at study completion (median 2.3 years) for subjects recruited from both trials. Results: Biomarkers were measured in 265 consecutive patients [age median 62.0 years (Q1-Q3: 55.0-68.0 years), males 83%] with at least one change from baseline value. Among these, biomarkers were available at both short- and long-term follow-up in 221 subjects. ANGPT2 increased significantly in V as compared to PL at 1-month follow-up in the total population (p=0.034), and in males in both post-MI (p=0.031) and NSTEMI subjects (p=0.012), respectively. ANGPTL4 increased (p=0.028) and PAI-2 decreased (p=0.025) significantly in the total population in favor of V at final FU. In the total post-MI subgroup and among males of that group, a short-term significant increase in ESEL in favor of V was observed, p=0.029 and p=0.018, respectively. Also, a transient significant increase in VWF (p=0.032) in favor of V was seen at one month in NSTEMI patients. Conclusions: Significant changes suggesting potential harmful effects in some biomarkers were observed during 1-month and long-term PAR-1 inhibition as compared to placebo in post-MI and acute coronary syndrome patients.

Background Vorapaxar has been shown to reduce cardiovascular mortality in post myocardial infarction (MI) patients. Pharmacodynamic biomarker research related to protease-activated receptor-1 (PAR-1) inhibition with vorapaxar in humans has short follow-up (FU) duration and is mainly focused on platelets rather than endothelial cells. Aim This article assesses systemic changes in endothelial-related biomarkers during vorapaxar treatment compared with placebo at 30 days' FU and beyond, in patients with coronary heart disease. Methods Local substudy patients in Norway were included consecutively from two randomized controlled trials; post-MI subjects from TRA2P-TIMI 50 and non-ST-segment elevation MI (NSTEMI) patients from TRACER. Aliquots of citrated blood were stored at-80 degrees C. Angiopoietin-2, angiopoietin-like 4, vascular endothelial growth factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, von Willebrand factor, thrombomodulin, and plasminogen activator inhibitor-1 and-2 were measured at 1-month FU and at study completion (median 2.3 years for pooled patients). Results A total of 265 consecutive patients (age median 62.0, males 83%) were included. Biomarkers were available at both FUs in 221 subjects. In the total population, angiopoietin-2 increased in patients on vorapaxar as compared with placebo at 1 month FU (p = 0.034). Angiopoietin-like 4 increased (p = 0.028) and plasminogen activator inhibitor-2 decreased (p = 0.025) in favor of vorapaxar at final FU. In post MI subjects, a short-term increase in E-selectin favoring vorapaxar was observed, p = 0.029. Also, a short-term increase in von Willebrand factor (p = 0.032) favoring vorapaxar was noted in NSTEMI patients. Conclusion Significant endothelial biomarker changes during PAR-1 inhibition were observed in post-MI and NSTEMI patients.

On top of standard antiplatelet therapy, vorapaxar reduces the risk of ischemic events or cardiovascular death in patients with stable coronary artery disease (CAD).[1] Vorapaxar is a selective antagonist of protease-activated receptor-1 (PAR-1), thereby blocking thrombin-mediated platelet activation.[2] [3] However, other actions of thrombin, such as fibrin formation and protein-C activation, are not inhibited by blocking PAR-1. Although vorapaxar probably does not affect the coagulation process directly, platelet inhibition leading to reduced availability of a procoagulant surface for the assembly of coagulation factors might lower the rate of thrombin formation indirectly. Therefore, the aim of this study is to assess whether the beneficial effect of vorapaxar on top of standard antiplatelet therapy in stable CAD patients can only be ascribed to more potent platelet inhibition or to an additional effect on thrombin generation.

Drug-induced liver injury is one of the major reasons for a drug to be withdrawn postmarketing. Carbamazepine (CBZ), an anticonvulsant agent, has been reported rarely to cause liver failure in humans. We recently generated a rat model of CBZ-induced liver injury using F344 rats for five consecutive days of CBZ administration combined with a glutathione (GSH) depletor, l-buthionine S,R-sulfoximine, treatment. The involvement of metabolic activation was demonstrated in developing CBZ-induced liver injury, and a difference in metabolic activation reactions between mice and rats was indicated. In this study, we analyzed the pathogenetic mechanism of CBZ-induced liver injury, primarily focusing on immune- and inflammation-related factors using the rat model for CBZ-induced liver injury. After the last CBZ administration, plasma alanine aminotransfearase (ALT) levels were drastically increased. In the histopathological evaluation, time-dependent hepatocellular degeneration and necrosis were observed in the centrilobular region. Different from mice, although hepatic mRNA expression levels of inflammation-related genes were increased, T-helper cell-related genes were not predominantly changed in rats. The number of ED1- and ED2-positive macrophages was increased in injured centrilobular areas in the liver with CBZ-induced liver injury. Treatment with a Kupffer cell depletor, gadolinium chloride, prevented the elevation of plasma ALT levels and an increase in the hepatic mRNA expression levels of inflammation-related genes. Hepatic adenosine triphosphate (ATP) contents were significantly decreased 24 h after CBZ administration. Therefore, the Kupffer cells-mediated inflammation was predominant in the development of the CBZ-induced liver injury in rats.

Autophagy modulation has been considered as a potential therapeutic strategy for lung diseases. The PI3K-Akt-mTOR pathway may be one of the main targets for regulation of autophagy. We previously reported that a PI3 K/mTOR dual inhibitor PF-04691502 suppressed hepatoma cells growth in vitro. However, it is still unclear whether PF-04691502 induces autophagy and its roles in DNA damage and cell death in human lung cancer cells. In this study, we investigate the effects of PF-04691502 on the autophagy and its correlation with cell apoptosis and DNA damage in non-small-cell lung cancer (NSCLC) cell lines. PF-04691502 efficiently inhibited the phosphorylation of Akt and showed dose-dependent cytotoxicity in A549 and H1299 cells. PF-04691502 also triggered apoptosis and the cleavage of caspase-3 and PARP. Phosphorylated histone H2AX (γ-H2AX), a hallmark of DNA damage response, was dramatically induced by PF-04691502 treatment. By exposure to PF-04691502, A549 cells acquired a senescent-like phenotype with an increase in the level of β-galactosidase. Furthermore, PF-04691502 enhanced the expression of LC3-II in a concentration-dependent manner. More interestingly, effects of PF-04691502 on toxicity and DNA damage were remarkably increased by co-treatment with an autophagy inhibitor, chloroquine (CQ), in human lung cancer cells. These data suggest that a strategy of blocking autophagy to enhance the activity of PI3 K/mTOR inhibitors warrants further attention in treatment of NSCLC cells.

Patients with pulseless electrical activity or refractory ventricular fibrillation have a very bad prognosis. Coronary angiography and angioplasty may be required to restore an effective circulation, but this must be performed whilst chest compressions are continued. The LUCAS chest compression device is suitable for this purpose. So far there are no reports on the effect of this device on coronary circulation in humans. We monitored the coronary perfusion pressure assessed invasively as the difference between the diastolic pressures at the coronary ostium and right atrium, and compared these pressures with coronary flow graded using the TIMI scale in 6 patients. In 4 out of 6 we found a satisfactory coronary artery perfusion pressure and TIMI grade 3 flow (normal) on coronary angiography. Two of these patients survived the first 24h. Two patients did not have a satisfactory perfusion pressure and adequate flow rate was not seen.

Background The expression of pregnancy-associated plasma protein A (PAPP-A) was identified by immunohistochemistry (IHC) in culprit atherothrombotic plaque specimens harvested from patients admitted with ST-segment elevation myocardial infarction (STEMI). Methods The atherothrombotic samples were collected from a consecutive cohort consisting of 20 individuals admitted with STEMI to Stavanger University Hospital, Norway, from 2005-2006, presenting angiographically with an acute thrombotic occlusion of a coronary artery characterized by TIMI flow 0. The atherothrombotic plaques were obtained by aspiration thrombectomy during percutaneous coronary intervention within 12 hours from the onset of symptoms and prepared for IHC analysis. Results In the IHC analysis staining for PAPP-A occurred in the extracellular matrix of the plaques and no evidence of staining for PAPP-A was found in the thrombi. Conclusion Our results indicate that in vivo PAPP-A is strongly expressed in atherothrombotic plaques harvested from patients admitted with STEMI, as documented by IHC. Trial registration biobankregisteret@fhi.no1846

INTRODUCTION:After changing our treatment regimen from thrombolytic therapy to primary percutaneous intervention (PCI), we decided to perform a real-life retrospective comparison of the results obtained by thrombolytic therapy in 2000 with the results obtained by primary PCI in 2004 at our center which has no on-site cardiac surgery.METHODS:All patients admitted with ST-elevation myocardial infarction (STEMI) during 2000 and 2004 were included in our study. The charts were scrutinized by one of the authors to ensure accurate information on diagnostics and timing. Relevant data, which were predefined, were noted and compared in patients treated during the two time-periods.RESULTS:During the year of 2000, 197 patients were admitted with STEMI. Thrombolytics were administered to 138 of these patients. During 2004, 175 patients were admitted with STEMI and PCI was performed in 173 of these patients. Door-to-needle time was 28min and door-to-balloon time 80min, respectively. In-hospital mortality was significantly reduced from 2000 to 2004 (19.3% vs 8.6%, p=0.003). 30 day-mortality was likewise reduced from 21.3% to 8.6%, (p=0.0001), and this difference remained significant after excluding patients not receiving thrombolytics in the year 2000. In-hospital stay was reduced from 9.4 to 6.4 days, (p<0.001). None of the patients required transfer to a tertiary center for acute coronary artery bypass grafting.CONCLUSION:Initiation of a primary PCI program at a center without on site cardiac surgery is associated with a substantial increase in number of patients offered reperfusion therapy and a significant reduction in morbidity and mortality.

After changing our treatment regimen from thrombolytic therapy to primary percutaneous intervention (PCI), we decided to perform a real-life retrospective comparison of the results obtained by thrombolytic therapy in 2000 with the results obtained by primary PCI in 2004 at our center which has no on-site cardiac surgery.All patients admitted with ST-elevation myocardial infarction (STEMI) during 2000 and 2004 were included in our study. The charts were scrutinized by one of the authors to ensure accurate information on diagnostics and timing. Relevant data, which were predefined, were noted and compared in patients treated during the two time-periods.During the year of 2000, 197 patients were admitted with STEMI. Thrombolytics were administered to 138 of these patients. During 2004, 175 patients were admitted with STEMI and PCI was performed in 173 of these patients. Door-to-needle time was 28min and door-to-balloon time 80min, respectively. In-hospital mortality was significantly reduced from 2000 to 2004 (19.3% vs 8.6%, p=0.003). 30 day-mortality was likewise reduced from 21.3% to 8.6%, (p=0.0001), and this difference remained significant after excluding patients not receiving thrombolytics in the year 2000. In-hospital stay was reduced from 9.4 to 6.4 days, (p<0.001). None of the patients required transfer to a tertiary center for acute coronary artery bypass grafting.Initiation of a primary PCI program at a center without on site cardiac surgery is associated with a substantial increase in number of patients offered reperfusion therapy and a significant reduction in morbidity and mortality.

We report three patients with the entire coronary origin arising from the right sinus of Valsalva. The first patient had a single right coronary ostium associated with a bi-leaflet aortic valve. The second patient was admitted with ST-elevation myocardial infarction (STEMI) for primary PCI. The third patient had 3 isolated ostia, all originating from the right sinus of Valsalva. Coronary anomalies are associated with increased mortality, depending on the myocardium at risk. A left main originating from the right coronary sinus is supplying a greater extent of the myocardium and is associated both with an increased incidence of symptoms and of sudden cardiac death. The possibility of such an artery anomaly should always be considered in young individuals with a history of chest pain or syncope.

Background Percutaneous coronary intervention (PCI) in nonemergent patients with coronary artery disease in hospitals without on-site cardiac surgery backup is still controversial. To prospectively evaluate a set of low procedural risk criteria for PCI, patients with stable or unstable angina were randomized to treatment in either a community hospital, which had all supportive services except for on-site cardiac surgery, or a regional surgical hospital 213 km away.Methods and results During a 4-year period, 609 (57%) of 1064 consecutive patients with stable or unstable angina who underwent coronary angiography at a teaching community hospital in Norway fulfilled the predefined low-risk criteria for PCI. The patients were randomized to treatment at either the community hospital (n=305) or at the regional hospital (n=304). The angiographic success rate (96% at both hospitals) and number of major periprocedural complications (overall 0.3%) were equal at the 2 hospitals. In particular, there were no deaths or need for urgent transfer to cardiac surgery. At 6 months of clinical follow-up, there was a significant higher major adverse cardiac event rate at the community hospital, compared with the regional hospital (6.9% vs 2.3%, respectively, P=.03) because of more repeat target vessel revascularizations. Improvement in angina functional class and exercise capacity was similar in both groups. The excluded high-risk PCI patients had higher 6-month major adverse cardiac event rate compared with all low-risk patients (8.4% vs 4.3%, respectively, P.=.01).Conclusion Selected nonemergent patients can, based on angiography, safely undergo PCI at hospitals without cardiac surgery backup. The angiographic selection criteria identified high-risk patients, which had worsened outcome at 6 months of follow-up.

Background - Angiotensin- converting enzyme ( ACE) inhibitors have been shown to attenuate left ventricular ( LV) enlargement in association with reducing mortality after myocardial infarction ( MI). Preclinical data suggest that angiotensin receptor blockers ( ARBs) may have similar structural and functional effects after MI. The Valsartan in Acute Myocardial Infarction ( VALIANT) Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV ejection fraction to a greater extent than captopril alone.Methods and Results - Six hundred ten patients enrolled in the main VALIANT study who experienced MI and evidence of LV dysfunction, heart failure, or both were enrolled in the VALIANT Echo study. Patients were randomized to receive valsartan 160 mg PO BID, captopril 50 mg PO TID, or valsartan 80 mg PO BID plus captopril 50 mg PO TID between 1 and 10 days after MI. Six hundred three patients had echocardiograms of sufficient quality for quantitative analysis. Echocardiograms were digitized, and endocardial borders were traced manually from 2 short- axis and 2 apical views. Ventricular volumes, ejection fractions, combined areas, and infarct segment length were measured, and changes in echocardiographic measures from baseline to 20 months were compared between treatment groups. Baseline clinical and echocardiographic characteristics were similar in the 3 treatment arms. The changes from baseline to 20 months in all echocardiographic parameters were similar in all 3 treatment arms. Baseline echocardiographic measures of ejection fraction, end- diastolic volume, and infarct segment length were highly predictive of outcomes including total mortality, death or hospitalization for heart failure, or death or any cardiovascular event ( heart failure, MI, stroke, resuscitated sudden death), even after adjustment for known covariates.Conclusions - Treatment with the ACE inhibitor captopril, valsartan, or the combination of captopril plus valsartan resulted in similar changes in cardiac volume, ejection fraction, and infarct segment length between baseline and 20 months after MI. Baseline echocardiographic measures were powerfully and independently predictive of all major outcomes.

Background— The elderly constitute an increasing proportion of acute myocardial infarction patients and have disproportionately high mortality and morbidity. Those with heart failure or impaired left ventricular left ventricular function after acute myocardial infarction have high complication and mortality rates. Little is known about outcomes with contemporary therapies in these patients. Methods and Results— The Valsartan in Acute Myocardial Infarction Trial (VALIANT) randomized 14 703 patients with heart failure and/or left ventricular ejection fraction <40% to receive captopril, valsartan, or both. Mortality and a composite end point, including cardiovascular mortality, readmission for heart failure, reinfarction, stroke, and resuscitated cardiac arrest, were compared for the age groups of <65 (n=6988), 65 to 74 (n=4555), 75 to 84 (n=2777), and ≥85 (n=383) years. With increasing age, 3-year mortality almost quadrupled (13.4%, 26.3%, 36.0%, and 52.1%, respectively), composite end-point events more than doubled (25.2%, 41.0%, 52.3%, and 66.8%), and hospital admissions for heart failure almost tripled (12.0%, 23.1%, 31.3%, and 35.4%). Outcomes did not differ between the 3 study treatments in any age group. Adverse events associated with captopril and valsartan were more common in the elderly and in patients receiving combination therapy. With increasing age, use of aspirin, β-blockers, and statins declined, and use of digoxin, calcium-channel blockers, and non–potassium-sparing diuretics increased. On 3-year multivariable analysis, each 10-year age increase was associated with a hazard ratio of 1.49 (95% CI, 1.426 to 1.557; P <0.0001) for mortality and an odds ratio of 1.38 (95% CI, 1.31 to 1.46; P <0.0001) for readmission with heart failure. Conclusions— Outcomes remained poor in elderly patients with heart failure and/or impaired left ventricular systolic function after acute myocardial infarction, although most received β-blockers and all received an ACE inhibitor and/or an angiotensin receptor blocker. Better therapies and increased use of aspirin, β-blockers, and statins are needed in this important and increasing patient group.

Recently, attention has been focused on late complications related to drug eluting stents (DES) [Farb A, Burke AP, Kolodgie FD, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation 108 (2003) 1701-6; McFadden EP, Stabile E, Regar E, Cheneau E, Ong AT, Kinnaird T, et al. Late thrombosis in drug-eluting stents after discontinuation of platelet therapy. Lancet 364 (2004) 1519-21; Eisenberg MJ. Drug-eluting stents: some bare facts. Lancet 364 (2004) 1466-7, [1-3]. We present two cases with late stent thrombosis (LST) and one case with a stent-related aneurysm. All patients were treated with the paclitaxel coated stent (Taxus-R) which is the most commonly used DES in our department.

The value of coronary angiography in unselected patients after myocardial infarction is still controversial. Our study includes 131 consecutive young patients (< 50 years old) in whom coronary angiography was performed after their first myocardial infarction. Angina pectoris was present in 71 (54%), and silent ischemia in 11 (9%): 49 patients (37%) were asymptomatic and without myocardial ischemia. Significant coronary artery stenosis was present in 119 patients (91%). A larger share of the patients with angina or silent ischemia than of those without had multivessel disease and high angiographic risk, and more of them were referred for revascularization. However, many of the asymptomatic patients with a negative result on the exercise test also had serious, high risk coronary heart disease, and needed revascularization. Thus, although the presence of angina or myocardial ischemia can identify a group of patients with serious coronary heart disease, the diagnostic precision is low, and if coronary angiography is not performed, many young patients with high risk disease may be overlooked.

BACKGROUND:Advances in the treatment of cardiovascular disease have increased costs; annual cardiovascular healthcare expenditure in the United States currently exceeds $100 billion. Physicians and third-party payers need to assess the economic impact of treatments that reduce cardiovascular morbidity and mortality.METHODS AND RESULTS:The Scandinavian Simvastatin Survival Study is a randomized, double-blind, placebo-controlled trial in which simvastatin reduced the risk of death by 30% (P=.0003) over the median follow-up period of 5.4 years in patients with previous myocardial infarction or stable angina pectoris as a result of a 42% reduction in the risk of coronary deaths (P=.00001). In the present report, data prospectively collected from hospital admissions were analyzed to evaluate the impact of simvastatin on healthcare resource use and perform a cost-minimization analysis. In the placebo group (n=2223), there were 1905 hospitalizations (average duration, 7.9 days) for acute cardiovascular events or coronary revascularization procedures among 937 patients, whereas in the simvastatin group (n=2221), there were 1403 such hospitalizations (average duration, 7.1 days) among 720 patients (all differences, P<.0001). The corresponding number of hospital days was 15089 and 9951 in the two groups, respectively (34% reduction,P<.0001). In the United States, the resulting reduction in hospitalization costs over the 5.4 years of the trial would be $3872 per patient, reducing the effective cost of simvastatin by 88% to $0.28 per day.CONCLUSIONS:In addition to reducing mortality and morbidity in coronary heart disease patients, simvastatin markedly reduces use of hospital services, thus offsetting most of its cost.