Can osteoprotegerin be used to identify the presence and severity of coronary artery disease in different clinical settings?

PURPOSE: The biomarker Osteoprotegerin (OPG) is associated with coronary artery disease (CAD). The main purpose of this study was to evaluate the diagnostic value of OPG in healthy subjects and in patients with suspected angina pectoris (AP). METHODS: A total of 1805 persons were enrolled: 1152 healthy subjects and 493 patients with suspected AP. For comparison 160 patients with acute myocardial infarction (MI) were included. To uncover subclinical coronary atherosclerosis, a non-contrast cardiac-CT scan was performed in healthy subjects; while in patients with suspected AP a contrast coronary angiography was used to detect significant stenosis. OPG concentrations were analyzed and compared between groups. ROC-analyses were performed to estimate OPG cut-off values. RESULTS: OPG concentrations increased according to disease severity with the highest levels found in patients with acute MI. No significant difference (p = 0.97) in OPG concentrations was observed between subgroups of healthy subjects according to severity of coronary calcifications. A significant difference (p < 0.0001) in OPG concentrations was found between subgroups of patients with suspected stable AP according to severity of CAD. ROC-analysis showed an AUC of 0.62 (95% CI: 0.57-0.67). The optimal cut-off value of OPG (<2.29 ng/mL) had a sensitivity of 56.2% (95% CI: 49.2-63.0%) and a specificity of 62.9% (95% CI: 57.3-68.2%). CONCLUSION: OPG cannot be used to differentiate between healthy subjects with low versus high levels of coronary calcifications. In patients with suspected AP a single OPG measurement is of limited use in the diagnosis of CAD.

Optimal cut-off value for cardiac troponin I in ruling out Type 5 myocardial infarction.

OBJECTIVES: The clinical classification of myocardial infarction (MI) into five types was introduced in 2007 as a component of the universal definition. A Type 5 MI was defined as a MI related to coronary artery bypass surgery. In a setting of patients undergoing elective coronary artery bypass grafting, we set out (i) to describe the pattern of multiple serial cardiac troponin I (cTnI) measurements within 72 h postoperatively and (ii) to determine the optimal cardiac troponin I cut-off value in ruling in or ruling out a Type 5 MI. METHODS: In 2011-2012, patients with two- and three-vessel disease scheduled for elective on-pump coronary artery bypass grafting were considered. Samples for cTnI were drawn before and 0, 2, 4, 6, 12, 24, 48 and 72 h after surgery. Analysis for cardiac troponin I was performed by use of the Abbott Architect c16000 system with an upper reference limit (URL) of 30 ng/l. The diagnosis of a Type 5 MI was prospectively made by a consultant cardiologist and was based on clinical, electrocardiographic and imaging data together with routine sampling and measurements of cTnI, but without knowledge of the results of serial study cTnI measurements. RESULTS: Of the 141 eligible patients, 99 (70%) qualified for final enrollment. In 8 patients (8%), the clinical diagnosis of a Type 5 MI was made. Patients without Type 5 MI (n = 91) had a median cTnI peak value of 7675 ng/l compared with 20 500 ng/l in Type 5 MI patients (P = 0.01). By use of receiver operating characteristic curves, optimal cut-off values for identifying Type 5 MI were defined as 7970 ng/l (corresponding to 266 times the URL) 12 h postoperatively and 9950 ng/l (corresponding to 331 times the URL) 24 h postoperatively. These cut-off values resulted in negative predictive values of 0.99 (12 h) and 0.99 (24 h). Positive predictive values were 0.23 (12 h) and 0.35 (24 h). CONCLUSIONS: In clinically stable patients undergoing elective coronary artery bypass grafting, measurements of cTnI are useful in ruling out a Type 5 MI.

Localization of microfibrillar-associated protein 4 (MFAP4) in human tissues: clinical evaluation of serum MFAP4 and its association with various cardiovascular conditions.

Microfibrillar-associated protein 4 (MFAP4) is located in the extracellular matrix (ECM). We sought to identify tissues with high levels of MFAP4 mRNA and MFAP4 protein expression. Moreover, we aimed to evaluate the significance of MFAP4 as a marker of cardiovascular disease (CVD) and to correlate MFAP4 with other known ECM markers, such as fibulin-1, osteoprotegerin (OPG), and osteopontin (OPN). Quantitative real-time PCR demonstrated that MFAP4 mRNA was more highly expressed in the heart, lung, and intestine than in other elastic tissues. Immunohistochemical studies demonstrated high levels of MFAP4 protein mainly at sites rich in elastic fibers and within blood vessels in all tissues investigated. The AlphaLISA technique was used to determine serum MFAP4 levels in a clinical cohort of 172 patients consisting of 5 matched groups with varying degrees of CVD: 1: patients with ST elevation myocardial infarction (STEMI), 2: patients with non-STEMI, 3: patients destined for vascular surgery because of various atherosclerotic diseases (stable atherosclerotic disease), 4: apparently healthy individuals with documented coronary artery calcification (CAC-positive), and 5: apparently healthy individuals without signs of coronary artery calcification (CAC-negative). Serum MFAP4 levels were significantly lower in patients with stable atherosclerotic disease than CAC-negative individuals (p<0.05). Furthermore, lower serum MFAP4 levels were present in patients with stable atherosclerotic disease compared with STEMI and non-STEMI patients (p<0.05). In patients with stable atherosclerotic disease, positive correlations between MFAP4 and both fibulin-1 (ρ = 0.50; p = 0.0244) and OPG (ρ = 0.62; p = 0.0014) were found. Together, these results indicate that MFAP4 is mainly located in elastic fibers and is highly expressed in blood vessels. The present study suggests that serum MFAP4 varies in groups of patients with different cardiovascular conditions. Further studies are warranted to describe the role of serum MFAP4 as a biomarker of stable atherosclerotic disease.

Osteoprotegerin as a marker of atherosclerosis: a systematic update.

OBJECTIVE: Osteoprotegerin (OPG) may be involved in development of atherosclerosis. To evaluate plasma concentrations of OPG in individuals with stable coronary artery disease (CAD), acute coronary syndrome (ACS), peripheral artery disease (PAD), and cerebrovascular disease (CBVD) a systematic literature review was performed. DESIGN AND METHODS: Studies investigating OPG concentrations in stable CAD, ACS, PAD, and CBVD were extracted from PubMed and the Cochrane Library, retrieving 280 articles. Nonrelevant articles were excluded and after thorough evaluation, and only 14 studies with clearly defined cohorts qualified for this review. RESULTS: In 11 studies, OPG concentrations were elevated. Severity of atherosclerosis was significantly associated with higher OPG concentrations compared to healthy controls. No association between PAD and OPG concentrations was observed. CONCLUSION: OPG concentrations are associated with the presence and severity of stable CAD, ACS, and CBVD. Larger studies are needed to reach conclusions concerning OPG concentrations in PAD. Studies addressing a putative role for OPG in suspected CAD and CBVD are warranted.

[Bleeding complications after treatment with clopidogrel and acetylsalicylic acid after acute coronary syndrome]. / Blødningskomplikationer ved behandling med clopidogrel og acetylsalicylsyre efter akut koronart syndrom.

INTRODUCTION: The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study showed that patients with unstable angina pectoris (UAP) and non-ST-elevation myocardial infarction (NSTEMI) benefit from combined therapy with acetylsalicylic acid (ASA) and clopidogrel. However, only patients entering clinical randomized trials were studied. We sought to assess whether the risk of bleeding increased after the introduction of the CURE criteria in an unselected population of Danish patients with NSTEMI or UAP. MATERIALS AND METHODS: The CURE criteria were implemented in the Department of Cardiology, Odense University Hospital, in December 2001. Two consecutive one-year periods were studied: period 1, December 2000-November 2001, and period 2, December 2001-November 2002. Patient charts were reviewed, and major bleeding complications and the primary clinical end point (non-fatal myocardial infarction, stroke or death) was registered. Follow-up took place one year later. RESULTS: In all, 290 patients were included in period 1 and 189 in period 2. During period 1, there were 12 (4.1%) and during period 2, 21 (11.1%) major bleeding events (odds ratio 3.07; 95% CI 1.42-6.65; p = 0.005). Compared with the patients treated with clopidogrel and ASA in the CURE study, we also found a three times greater risk of major bleeding in period 2. In particular, patients over 70 years of age and patients undergoing bypass surgery were at heightened risk. The incidence of the primary clinical end point was higher in both period 1 and period 2 than in the CURE study. CONCLUSION: Our study demonstrates an increased risk of major bleeding in unselected patients receiving combination therapy with ASA and clopidogrel after UAP or NSTEMI. Major bleeding complications most frequently occur in patients above 70 years of age and following bypass surgery.

[Coronary angioplasty and coronary artery bypass surgery in older patients. Incidence, complications and mortality, 1999-2003]. / Ballonbehandling og koronar bypasskirurgi hos aeldre. Forekomst, komplikationer og mortalitet 1999-2003.

INTRODUCTION: Persons over 70 years of age are the fastest-growing segment of the population. A major proportion of these elderly have ischemic heart disease and may need treatment. We describe the development of mechanical coronary revascularization in patients aged 70-79 years versus those 80 years of age or older over a five-year period. MATERIALS AND METHODS: During 1999, 2001 and 2003, a total of 774 patients over 70 years of age had coronary angioplasty (PCI) or coronary artery bypass surgery (CABG) performed at Odense University Hospital. The patients were separated according to type of intervention and age: 70-79 versus > or = 80 years of age. Retrospectively, descriptive characteristics, complication rates and six-month mortality rates were compiled. RESULTS: During the study period, the number of interventions increased from 182 to 374 per year. In the patients > or = 80 years of age, a tenfold increase in the number of procedures was noted, whereas the frequency in the younger patients was approximately doubled. During the five-year period, the proportion of CABGs performed was stable, but the frequency of PCIs increased by a factor of five. Over time, the number of acute interventions increased. Patients > or = 80 years of age more frequently had complications than did patients 70-79 years of age. The six-month mortality rate increased throughout the study period and was highest in patients > or = 80 years of age. CONCLUSION: During the five-year period from 1999 to 2003, the total number of coronary revascularizations in the elderly increased. The main reason for this was a marked increment in the use of PCIs and a general increase in the use of revascularizations in patients 80 years of age or older. PCI in the elderly is associated with a lower frequency of complications.