Tina Svenstrup Poulsen

Classification of Myocardial Infarction: Frequency and Features of Type 2 Myocardial Infarction

BACKGROUND The classification of myocardial infarction into 5 types was introduced in 2007 as an important component of the universal definition. In contrast to the plaque rupture-related type 1 myocardial infarction, type 2 myocardial infarction is considered to be caused by an imbalance between demand and supply of oxygen in the myocardium. However, no specific criteria for type 2 myocardial infarction have been established. METHODS We prospectively studied unselected hospital patients who had cardiac troponin I measured on clinical indication. The diagnosis and classification of myocardial infarction were established, and the frequency and features of type 2 myocardial infarction were investigated by use of novel developed criteria. RESULTS From January 2010 to January 2011, a total of 7230 consecutive patients who had cardiac troponin I measured were evaluated, and 4499 patients qualified for inclusion. The diagnosis of myocardial infarction was established in 553 patients, of whom 386 (72%) had a type 1 myocardial infarction and 144 (26%) had a type 2 myocardial infarction. Patients in the group with type 2 myocardial infarction were older and more likely to be female, and had more comorbidities. The proportion of patients without significant coronary artery disease was higher in those with type 2 myocardial infarction (45%) than in those with type 1 myocardial infarction (12%) (P < .001). Tachyarrhythmias, anemia, and respiratory failure were the most prevalent mechanisms causing type 2 myocardial infarction. CONCLUSIONS In a cohort of patients with myocardial infarction who were admitted consecutively through 1 year, the category of type 2 myocardial infarction comprised one fourth when diagnosed by the use of newly developed criteria. Approximately half of patients with type 2 myocardial infarction had no significant coronary artery disease.

Mortality rate in type 2 myocardial infarction: Observations from an unselected hospital cohort

BACKGROUND The classification of myocardial infarction into 5 types was introduced in 2007. The prognostic impact of this universal definition, with particular focus on type 2 myocardial infarction, has not been studied prospectively in unselected hospital patients. METHODS During a 1-year period, all hospitalized patients having cardiac troponin I measured were considered. The diagnosis of a myocardial infarction was according to the universal definition, and specified criteria were used in the classification of type 2 myocardial infarction. Follow-up was at least 1 year, with mortality as the end point. RESULTS A total of 3762 consecutive patients were studied, of whom 488 (13%) had a myocardial infarction. In 119 patients a type 2 myocardial infarction was diagnosed. After a median of 2.1 years (interquartile range, 1.6-2.5 years), 150 patients had died, with a mortality rate of 49% (58/119) in those with type 2 myocardial infarction and 26% (92/360) in those with type 1 myocardial infarction (P < .0001). In a multivariable Cox regression analysis the following variables were independently associated with mortality: current or prior smoker, high age, prior myocardial infarction, type 2 myocardial infarction, hypercholesterolemia, high p-creatinine, and diabetes mellitus. The multivariable-adjusted hazard ratio for type 2 myocardial infarction was 2.0 (95% confidence interval, 1.3-3.0). With shock as the only exception, mortality was independent of the triggering conditions leading to type 2 myocardial infarction. CONCLUSIONS Mortality in patients with type 2 myocardial infarction is high, reaching approximately 50% after 2 years. Further descriptive and survival studies are needed to improve the scientific evidence on which treatment of type 2 myocardial infarction is based.

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.

The antiplatelet effect of clopidogrel is not attenuated by statin treatment in stable patients with ischemic heart disease

Recent studies suggest that cytochrome P450 (CYP) 3A4 metabolized statins attenuate the antiaggregatory effect of clopidogrel. We evaluated how CYP3A4 metabolized statins and non-CYP3A4 metabolized statins influence platelet aggregation when given concomitantly with clopidogrel. Sixty-six stable patients with ischemic heart disease were included in this parallel group study. All patients were on clopidogrel and aspirin. Thirty-three patients received a CYP3A4 metabolized statin (simvastatin or atorvastatin), and 33 were treated with a non-CYP3A4 metabolized statin (pravastatin). The antiplatelet effect of clopidogrel was assessed at inclusion and 21 days after statin discontinuation. Platelet function was evaluated by two methods 1) optical platelet aggregometry after stimulation with 20 and 30 microM ADP, and 2 and 4 mg/l collagen, respectively, 2) a Platelet FunctionAnalyzer-100. The primary effect measure was final platelet aggregation after stimulation with 20 microM ADP. No difference was observed between patients treated with a CYP3A4 metabolized statin and patients receiving a non-CYP3A4 metabolized statin (30% point (7-42) versus 20% point (9-32), p = 0.83). Platelet aggregation was not improved by discontinuation of statins for 21 days. Indeed, we found that statin treatment given concomitantly with clopidogrel resulted in an improved platelet inhibition when compared to clopidogrel given alone. The antiplatelet effect of clopidogrel is not attenuated by concomitant treatment with a CYP3A4 metabolized statin in patients with clinical stable ischemic heart disease.

Clinical Characteristics and Outcomes of Patients with Myocardial Infarction, Myocardial Injury, and Nonelevated Troponins

BACKGROUND Cardiac troponins have emerged as the preferred biomarkers for detecting myocardial necrosis and diagnosing myocardial infarction. However, current cardiac troponin assays do not discriminate between ischemic and nonischemic causes of myocardial cell death. Thus, when an increased troponin value is encountered in the absence of obvious myocardial ischemia, a careful search for other clinical conditions is crucial. METHODS In 2010 to 2011, we prospectively studied hospitalized patients who had cardiac troponin I measured on clinical indication. An acute myocardial infarction was diagnosed in cases of a cardiac troponin I increase or decrease pattern with at least 1 value >30 ng/L (99th percentile) together with myocardial ischemia. Myocardial injury was defined as cardiac troponin I values >30 ng/L, but without signs or symptoms indicating overt cardiac ischemia. Patients with peak values ≤30 ng/L were classified as nonelevated cardiac troponin I. Follow-up was at least 3 years with all-cause mortality as the sole clinical end point. RESULTS A total of 3762 patients were included. Of these, 488 (13%) had acute myocardial infarction, 1089 (29%) had myocardial injury, and 2185 (58%) had nonelevated cardiac troponin I values. Patients with myocardial injury frequently presented with dyspnea, were older, and had more comorbidity than patients in the 2 other groups. During a median follow-up of 3.2 years, 1342 patients died. Mortality differed significantly between groups: 39% in those with myocardial infarction, 59% in those with myocardial injury, and 23% in those with nonelevated cardiac troponin I (log-rank test; P < .0001). No significant difference in mortality between patients with type 2 myocardial infarction and patients with myocardial injury was observed (63% and 59%, respectively). CONCLUSIONS Patients with myocardial injury are older and have more comorbidity than those with acute myocardial infarction. Both groups exhibit a poorer prognosis than patients with nonelevated cardiac troponin I values. Of note, a very high long-term mortality is observed in patients with type 2 myocardial infarction and patients with myocardial injury.

Plasma osteoprotegerin is related to carotid and peripheral arterial disease, but not to myocardial ischemia in type 2 diabetes mellitus

BackgroundCardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes.MethodsType 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured.ResultsThe prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia.ConclusionsIncreased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown.Trial registration numberat http://www.clinicaltrial.gov: NCT00298844

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

Abstract 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.

A Critical Appraisal of the Phenomenon of Aspirin Resistance

Aspirin is the mainstay antiplatelet treatment in patients with high risk of cardiovascular atherothrombotic events, and its beneficial effect is documented in several clinical trials. Nevertheless, the effectiveness of aspirin has been questioned by the emergence of the concept of ‘aspirin resistance’ (AR). This phenomenon, although lacking a precise definition, covers the fact that some patients do not exhibit the expected platelet inhibition by use of various techniques for measuring platelet function. In this critical review, we evaluate the methods used for measuring AR. We will discuss the available data regarding the prevalence and the clinical importance of the phenomenon. Finally, the potential mechanisms underlying AR are considered.

Monitoring aspirin therapy with the Platelet Function Analyzer‐100

Objective. Low platelet response to aspirin has been reported to be associated with a high incidence of vascular events. The reported prevalence of aspirin low‐responsiveness varies, which may be explained by poor reproducibility of the methods used to evaluate aspirin response and low compliance. The Platelet Function Analyzer‐100 (PFA‐100) is a commonly used platelet function test. We aimed to assess the reproducibility of the PFA‐100 and the agreement with optical platelet aggregometry (OPA) in healthy volunteers and in patients with coronary artery disease (CAD) treated with low‐dose aspirin. Material and methods. Twenty‐one healthy volunteers and 43 patients with CAD took part in the study. During treatment with aspirin 75 mg daily, all participants had platelet function assessed in duplicate with the PFA‐100 and OPA on 4 consecutive days. Additionally, platelet function was assessed before aspirin treatment in healthy subjects. Serum‐thromboxane B2 (S‐TxB2) was measured to assess compliance. Results. In healthy volunteers not receiving aspirin, duplicate measurements resulted in coefficients of variation (CV) of 7.9 % for the PFA‐100 and 5.2 % for OPA. During aspirin treatment, CVs were significantly higher (healthy volunteers: PFA‐100: 15.6 %, OPA: 19.2 %; patients: PFA‐100: 26.6 %, OPA: 16.8 %). Two of the 64 participants were classified as aspirin low‐responders with both methods, indicating poor agreement (Kappa coefficient 0.05). Compliance was excellent, as S‐TxB2 was completely inhibited in all participants. Conclusions. Aspirin treatment affects the reproducibility of both PFA‐100 and OPA. This imprecision should be considered carefully if the methods are used for monitoring aspirin treatment. Additionally, these methods do not identify the same individuals as being aspirin low‐responders.