The Effect of Protease-Activated Receptor-1 (PAR-1) Inhibition on Endothelial-Related Biomarkers in Patients with Coronary Artery Disease.

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°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.

Coronary blood flow and perfusion pressure during coronary angiography in patients with ongoing mechanical chest compression: a report on 6 cases.

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.

The activity of pregnancy-associated plasma protein A (PAPP-A) as expressed by immunohistochemistry in atherothrombotic plaques obtained by aspiration thrombectomy in patients presenting with a ST-elevation myocardial infarction: a brief communication.

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.

Change to a primary PCI program increases number of patients offered reperfusion therapy and significantly reduces mortality: a real life experience evaluating the initiation of a primary PCI service at a single center without on site heart surgery in Western Norway.

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.

Mitral regurgitation in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: prognostic significance and relation to ventricular size and function.

AIMS: Mitral regurgitation (MR) confers independent risk in patients with acute myocardial infarction. We utilized data from the VALsartan In Acute myocardial iNfarcTion echo study to relate baseline MR to left ventricular (LV) size, shape, and function, and to assess the relationship between baseline MR and progression of MR and cardiovascular (CV) outcomes. METHODS AND RESULTS: We studied 496 patients with heart failure (HF) and/or systolic dysfunction after MI who underwent echocardiography at a median of 5 days after MI. MR severity, quantified as the regurgitant jet area/left atrial area ratio, was assessed at baseline, one and 20 months post-MI and related to LV size, shape, function, and clinical outcomes. Increased MR at baseline was associated with larger LV end-diastolic and end-systolic volumes, increased sphericity index, and reduced ejection fraction (P trend < 0.001). Moderate-severe MR was an independent predictor of total mortality [adjusted hazard ratio (HR) 2.4 (1.1-5.3)], CV mortality [adjusted HR 2.7 (1.2-6.1)], hospitalization for HF [adjusted HR 2.5 (1.1-5.5)], or death or HF hospitalization [adjusted HR 2.5 (1.4-4.6)]. Patients with progression of MR during the first post-MI month were substantially more likely to die or develop HF (adjusted HR per increased MR grade 3.0, 95% CI 1.8-4.9). Progression of MR over 20 months in survivors was associated with increased hospitalizations for HF (P < 0.001). CONCLUSION: Following high-risk myocardial infarction, baseline mitral regurgitant severity is associated with larger LV volumes and worse LV function. Both baseline MR severity and progression of MR are associated with an increased likelihood of adverse outcomes.

Anomalies of the coronary arteries originating from the right sinus of Valsalva. (1) Single coronary artery originating from the right sinus associated with fusion of the left and the non coronary cusp and atrophy of the left coronary ostium (2)Three separate coronary arteries originating from the right sinus of Valsalva.

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.

Nonemergent coronary angioplasty without on-site surgical backup: a randomized study evaluating outcomes in low-risk patients.

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 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 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.

Late complications following the deployment of drug eluting stents.

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.

Mortality and morbidity remain high despite captopril and/or Valsartan therapy in elderly patients with left ventricular systolic dysfunction, heart failure, or both after acute myocardial infarction: results from the Valsartan in Acute Myocardial Infarction Trial (VALIANT).

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 > or =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, beta-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 beta-blockers and all received an ACE inhibitor and/or an angiotensin receptor blocker. Better therapies and increased use of aspirin, beta-blockers, and statins are needed in this important and increasing patient group.

Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction.

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.